Natural Resources and Energy Paper

Natural Resources and Energy Paper Spechelle Jones, Cherrie Chicaletto, Robert Hernandez, Jamie Hughes SCI/256 October 13th, 2010 The world is growing at a rate of speed of 2. 8 people per second and losing 1. 6 acres of land per second in accordance with an article last month titled Environmental Impacts from Unsustainable Population Growth on the World Population Awareness website. World Population Awareness is an organization concerned with recent problems of as well as solution ideas to popular global warming theories caused directly by overpopulation of the world. (World, 2010).In addition to all natural resources on this planet fading away, there is an ever growing apprehension with the number of species of wildlife and the respective habitats of each. All over the world, nature preservation parks have been constructed just so a small group of people can be accountable to enforce certain guidelines for that preserve which support and ensure safety of life within that area. With more and more natural resources required to maintain our â€Å"natural† function of life, it is inevitable that the natural resources will run out sometime. It is only a question of when.E. O. Wilson said, â€Å"The one process ongoing †¦ that will take millions of years to correct is the loss of genetic and species diversity by the destruction of natural habitats. This is the folly our descendants are least likely to forgive us. † This theory has been the fuel for the modern â€Å"Go Green† campaign. Individuals everywhere have formed organizations promoting new resources that do not compromise the state of our planet. Ideas are being televised worldwide to educate people and suggest new ways of heating our homes or washing our clothes with a new detergent.With this in mind, it could only be a matter of time before the government requires everyone to follow certain procedures for the disposal of waste or building a house. Suddenly, it just does not seem s o important anymore that the government may be infringing on our rights as an American citizen to force regulatory guidelines. Taking the place of this common concern, is a universal interest and effort to save our planet for the sake of our children. Renewable forest resources are declining due the increased use of nonrenewable forest resources.Coal and natural gas are two examples of nonrenewable forest resources. These resources are nonrenewable because they cannot be recycled. The high abundance of coal and natural gas hit its peak one hundred years ago, after sitting under the earth for more than an estimated one million years. The supply of coal and natural gas is nearly gone due to excessive use of the resources in the past century. The coal and natural gas is not renewable; these resources are causing pollution to the ocean and all waters alike.Extracting natural gas and oil from forests for energy source is convenient to humans, but the environment is suffering as well as t he natural resources that are part of the local ecosystem of the forest. The forest resources were so abundant; however the transformation to these natural lands is irreversible. The forests can provide natural resources for centuries to come (Derr, 2007). Proper management of these resources is necessary for renewable forest resources. Water, air and paper are all examples of renewable forest resources.However, once these resources are polluted by the other resources; it is much more difficult to recycle them. In many cases, it is just too late to recycle those items because of the high amount of pollutant they had sustained. Carbon Dioxide is recycled into clean oxygen by plants and trees. Since many trees are being cut down and burned, more charcoal is being produced; which is a nonrenewable resource. The trees are being cut down, which can leave renewable forest resources.However, many of the trees in these big forests have been growing for thousands of years. The strength and p ower of these trees is impossible to regain. The trees have been putting clean oxygen into the air for thousands of years. New trees begin growing each year with the seeds from those who were cut down. None of those trees will have near the amount of power and/or shelter important to the surrounding ecosystem like those who had been growing for hundreds of years. It is vital to the local ecosystem of the forests that the trees remain.Animals do not want paper for shelter, nor can paper produce clean air to breath. It is important that the natural resources be taken care of, too much of the natural resources are depleting too quickly.References Derr, A. (2007). RENEWABLE RESOURCES. Boys' Life, 97(3), 38. Retrieved from MasterFILE Premier database. World Population Awareness. (2010). Environmental Impacts from Unsustainable Population Growth. Retrieved from Google at http://www. overpopulation. org/impact. html. Natural Resources and Energy Paper Natural ecosystem is a natural unit consisting of all plants, animals, and microorganism in an area functioning together with all the non-living physical of the environment which plants and animals are dependent upon one another, and their particular surroundings-for survival. Natural ecosystems make up the planet on which we live as well as the entire universe. They are dynamic and interconnected. An ecosystem is a collection of all plants, animals, microorganisms, bacterium, and fungus as well as the non-living components that function together as one unit in a given area (The Ontario Plan, 2011). Living and non-living things intertwine with each other in a natural ecosystem. San Diego’s wetland is an example of a natural ecosystem. In this paper it will discuss about the effects that a growing human population may have impacted on San Diego’s wetland’s resources, including loss or harm to populations of wild species. It would also discuss one management practice for sustainability and conservation of natural resources. Also to identify the risks and benefits of extracting or using one resource from this ecosystem, or in any areas near this ecosystem. Effects of Human Population Coastal Wetlands are one of many endangered habitat in the world, only next to tropical rain forests. It is said that in the United States there are estimated more than 50% of wetlands have been severely altered or destroyed. San Diego wetland is the most threatened resource on the California coast. By 1900, wetlands have been affected by human activities. Wetlands everywhere have been filled in for human developments such as housing, industrial plants, and airport. They have been dredge for use as canals, waterways, and marinas. Highways are over the streamside canyons and cut right through coastal marshes, causing habitat fragmentation (Sea World, 2002). Loss and harm to population of wild species Between 1990 and 2000 wetland loss was approximately 24 square miles per year, which is one football field lost every 38 minutes. The loss over the next 50 years with current restoration efforts is expected to be 500 square miles. Human activities cause wetland degradation and loss by changing water quality, quantity, or flow rates resulting increasing pollution and change the makeup of species within a habitat. These changes occur when wetland ecosystems are disturbed or non-native species are introduced to a habitat. Wetland plants can suffer as a result of both pollution and hydrologic changes. Other ways wetland plants can be damaged are cattle and other livestock grazing, introduction of non-native plants that compete with native plants and removal of plants to use land for other human development. Management for sustainability and conservation In the 1970s and 80s state and federal agencies, together with many private conservation groups, spent millions of dollars to purchase San Diego County wetlands to establish wildlife preserves. As a result, most of the county’s wetlands are publicly owned. This has largely stopped the filling, dredging, and other direct destruction of the wetlands, but they are still suffering from the erosion and sedimentation caused by upstream development. The City of San Diego has recently restored seven acres of salt marsh on the north end of Mission Bay, which expands the wetlands of Mission Bay Northern Wildlife Preserve. The Southern California Wetlands Recovery Project aims to acquire more than 1,500 acres, and to restore or enhance more than 500. In San Diego County the Project includes 20 acres of restored salt marsh in the Tijuana River Estuary (Sea World, 2002). Nonrenewable and renewable energy Oil and coal are currently the most used forms of nonrenewable energy. Coal is a combustible material that comes from the earth. It is obtained from mining and is the most difficult resource to get. Oil is another combustible energy obtained from drilling, although unlike coal, once the hole is drilled the oil can be pumped out of the hole. This makes it easier and more cost effective to gather oil then coal (Oracle ThinkQuest, 2011). No risk or benefit found by extracting or using a nonrenewable type of resources. Renewable energy is energy that automatically replenishes itself from ongoing natural processes. For example, sunshine, wind, flowing water, biological processes, and geothermal heat flows are creators of usable renewable energy (Oracle ThinkQuest, 2011). Wetlands cannot use any of none or renewable energy because wetlands are very sensitive that anything alien expose or introduce to it would lead fragmentation or even damage. View as multi-pages

Araby vs. a & P

Celeste Stroup Interpretative Exercise 10/1/12 Araby vs. A&P Araby, written by James Joyce, and A&P, written by John Updike are two short stories that are a lot alike yet still completely different. Araby and A&P are both about young boys who are learning about love as they transition into adulthood. They both fall head over heels ‘in love’ with girls they have never met before. Both boys go to extremes measures to win over the love of the girls and be their hero’s. However, throughout both stories a couple of things were different.Such as, the passage of time in which the stories were written. Also, they had different circumstances that lead to the characters epiphany. And lastly, the use of dialogue was different in each short story. In A&P the time of passage is very important to developing the character of Sammy. The story of A&P was very time oriented. The whole story took place in a matter of a mere half an hour or so. This shows that Sammy’s feeling for this girl developed quickly and he appeared to have no control over his thought or actions. In Araby, the time orientation is much different.Unlike A&P, in Araby you don’t have a certain time frame. For example, on page 328 of â€Å"The Literary Experience,† Joyce writes â€Å"One evening I went into the back drawing room in which the priest had died. † The words ‘one evening’ are not very specific. Was it a day, a week, a month or even a year later! This could symbolize how the boys love for Mangan’s sister developed more and more over time rather than in a couple of minutes like Updike’s Sammy. In both stories, each boy comes to an epiphany at the end. However, different circumstances lead to them.In A&P, the mere presences of the three girls in the grocery store for such a short amount of time pushes Sammy. The ‘Queen Bee’ catches his attention and immediately captures his mind and heart. The presence and actions of her cause Sammy to quit his job and go chasing after this girl. When he sees that they left without turning back Sammy realizes that his life is going to be a lot harder from then on out and he is going to have to work at life, and girls, a lot harder. He can’t just drop everything and go chasing after them. Like in A&P, the boy in Araby is also extremely fixated on a girl who is out of his league.However, unlike Sammy, the boy is more patient with his actions and less hasty. He carefully plans out his moves so that he can be in her presence more. Over an unknown period of time he watches Mangan’s sister and gets to know her from afar. It isn’t until he goes to the bizarre to buy her a gift, does he realize how absurd he is being. How he has no chance with her and he is just fantasizing over something that he can’t have. While standing in the middle of the bizarre the boy comes to the realization that he has a lot of growing up to do. Lastly, dialogue pl ays a key role in how a character is seen.For example, in A&P, Sammy speaking in a nature of a typical teenage boy his age. He uses slang words help the reader recognize that his maturity level is average this helps us understand how his brain works and why he does what he does. But, the dialogue in Araby tells a whole different story. The young boy’s thoughts and actions are very advanced for his young age of 12 or 13. He is very good with his interpersonal skills that help him think through different scenarios. In both stories dialogue is a key part in understanding the characters actions.A conclusion that could be drawn from analyzing the parallels between the two stories is how on the surface the two stories appear to be the same; to love struck boys seeking out love as they come of age. However, as you did deeper, you soon realize how different they really are. They both have different underlying messages that wouldn’t be uncovered without analyzing the different literary elements. That is why close-reading is so important when trying to understand important themes or concepts. A lot of times they are hidden within the text and you have to dig deep to find them.

Identify the historical and cultural factors Essay

Identify the historical and cultural factors that contribute to the development of the learning perspective. To what extent is the learning perspective relevant today?  The study of how humans learn is a dominant component of the learning perspective. The study of behaviour in this perspective and is also commonly known as the Behaviouristic Approach, as they believe that behaviour is the only valid data in psychology. Behaviourism developed simultaneously in the United States and Russia in relation to many factors. Traditional Behaviourists believed that all organisms learn in the same way, and could be explained by the processes of classical and operant conditioning. Learning can be defined as a relatively permanent change in behaviour and/or knowledge that occurs as a result of practice and/or experience in the environment. Psychologists working within this perspective have investigated he ways in which behaviour changes, usually using laboratory experiments, and often-using non-human animals. The Learning perspective developed simultaneously in the United States and Russia with American Theorists John Watson, Albert Bandura and Russian physiologist Ivan Pavlov.  The way in which behaviour can be observed is seen as being objectively or unbiased, and this is the opposite to the theory of introspection. The unreliability of the way in which subjective data is obtained in introspection is one of the main criticisms that lead to the rise of behaviourism. In introspection the data collected in said to be subjective and therefore biased in the sense that it comes from ones own mind. â€Å"Give me a dozen healthy infants†¦and my own specified world to bring them up in and I’ll guarantee to take any one at random and train him to become any type of specialist I might select – doctor, lawyer†¦and yes, even beggarman and thief.†1  John Watson 1913  Watson wrote an article titled ‘Psychology as the behaviourist views it.’ This article, which set out all main assumptions and principles, sparked the rise of the behaviourist movement in 1913. Albert Bandura was the major motivator behind the social learning theory, which included cognitive factors that were not incorporated by behaviourists, as they thought behaviour was almost entirely determined by the environment. Bandura suggests that much behaviour, including aggression, is learnt from the environment through reinforcement and the process of modelling. Bandura integrated cognitive influences and called his modified theory the social learning theory. Ivan Pavlov, a Russian physiologist, whilst conducting experiments on the digestive systems on dogs stumbled across the developed principles of classical conditioning. All these factors contributed to the advancement of the learning perspective, as we know it today. Key concepts of the perspective are classical and operant conditioning, social, latent and insight learning. All concepts are built from the historical and cultural factors that gave rise to the learning perspective. Findings after conduction of experiments show a remarkable relevance to today’s society and knowledge. Whether it is classical conditioning and relating findings to aversion therapy or operant conditioning’s relation to animal training or modifying behaviour through reinforcement and punishment. Therefore it is important to research experimenters who performed relevant experiments to relate their results to today. Classical condition is learning through association, which was accidentally found by Russian physiologist Ivan Pavlov. Pavlov was conducting experiments in relation to dogs digestive systems when he stumbled on, what is known as, classical conditioning. Pavlov noticed that dogs did not only salivate when food was placed in front of them, but they also salivated before the food was given to them, and was triggered by other factors such as upon hearing or seeing Pavlov, or the sound of footsteps. Pavlov then discovered that the anticipation of receiving the food made the dogs salivate. Pavlov then modified his experiment to test whether using a stimulus such as meat powder, which caused salivation, could be varied and a conditioned stimulus such as the ringing of a bell could also bring about the unconditioned response of salivation originally caused by being presented with the sight of the meat powder. Pavlov used a soundproof room, to minimise and limit extraneous variables so he could be sure that it was i.e. only the ringing of a bell that was affecting the salivation after the conditioned stimulus. John Watson performed another example of classical conditioning when he experimented on Little Albert in 1920. Behaviourists learning theorists such as Watson suggested that phobias were conditioned emotional responses. Certain stimuli, such as sudden loud noises, naturally cause fear reactions, and stimuli that become associated with them will acquire the same emotional responses. Little Albert was presented with a white laboratory rat to which he showed no fear response. Watson then associated the loud noise simultaneously with the presentation of the rat, Little Albert then associated fear with the rat, and was then able to generalise these response to other fluffy white objects. The study with Little Albert has serious ethical problems. Firstly that he participated in the experiment involuntary and without the consent of his mother. Also Watson reported that they hesitated about proceeding with the experiment but comforted themselves that Albert would encounter such traumatic associations when he left the sheltered environment of the nursery anyway. This is not a very good ethical defence, especially since they believed such associations might persist indefinitely and did not leave sufficient time to remove the fear afterwards, despite knowing that Albert was due to leave. Classical conditioning can be related to today with the development of therapies using classical conditioning techniques to extinguishing fear. The first technique of therapy is the systematic desensitation, which aims to extinguish the fear response of a phobia, and substitute a relaxation response to the conditional stimulus gradually, step by step. This therapy was developed mainly by Wolpe, who stated that in order for the fear to be removed gradually, a hierarchy of fear must be formed and ranked by the subject from least fearful to most fearful. The subject is then given training in deep muscle relaxation techniques so it can then be used at each stage of the hierarchy starting from the least fearful to the most and only progressing when the subject feels sufficiently relaxed. This method of treatment has a very high success rate with specific phobias, i.e. of particular animals. It is considered to work particularly well because the response of fear and relaxation is said to be impossible for them to exist at the same time. The second techniques of therapy are implosion and the flooding techniques, when both methods produce extinction of a phobia’s fear by the continual and dramatic presentation of the phobic or situation. Wolpe in 1960 forced a girl with a fear of cars into the back seat of a car and drove her around for 4 hours straight until her hysterical fear completely disappeared. Marks et al (1981) say that this kind of therapy works because eventually some stimulus exhaustion takes place, as you cannot scream forever and then the conditioned fear response extinguishes. The technique most similar to classical conditioning is called Aversion Therapy, and is most relevant to today’s treatment of alcoholism, smoking or overeating. The technique aims to remove undesirable responses to certain stimuli by associating them with aversive stimuli, in the hope that the undesirable responses will be avoided in the future. Aversion therapy has been used to treat alcoholism, for example the person is given alcohol with a nausea-inducing drug unsuspectingly, and should then feel sick. The person associates drinking with their intestinal distress and results found that two out of three people did not have any alcohol a year later. Although it has a high success rate, ethical considerations of deliberating causing discomfort to another person through deception must be taken into account. The limitation of this type of therapy is its difficulty to generalise to other situations from where the learning took place.

How to Get Over a Disappointment Essay Example | Topics and Well Written Essays - 1750 words

How to Get Over a Disappointment - Essay Example Disappointments manifest themselves in one’s thoughts, perception, will, emotions, imaginations and in our memory according to how we deal with situations. One can get over these through: total make up of the mind, figuring out how to avoid the same in future, stopping going over the details, getting engrossed in something fun and taking the disappointment in stride. First, one should always make up his mind in an event when disappointment strikes. It is healthy to draw your mind into conscious thinking, to wish away the past and accept what the future. Once a disappointment hits, what follows is remembrance. Constant thinking about dissatisfaction inputs people’s mind into regretful memoirs. No matter what happens one must try to forget it as first as possible. Making up ones mind to move on is the best starting point for every disappointment. Studies have shown that continual thinking of something that one loves or wishes for generates intense and strong feelings about it. Therefore, in the event that one falls short in his desire, then the windows of disappointment open up. For example, if one separates from his lover, the first positive move one should make is making up his mind to come into terms with his decision. One should stop thinking about the other and incline in the mental atmosphere that things will turn better. It is also healthy to find fault in one’s desired wish in order to distract the temptations of going back to that disappointment. It is only through the mind that we can get over the disappointment. What we allow into our heart, through our subconscious brain reflects in individuals physical being. This explains why some people will ease themselves out of any disappointment they come across while others will develop cold and frustrations upon every slight disappointment they encounter. Therefore, it is rational to involve thinking and reasoning whenever disaster strikes. Once we make up mind that indicates we have

Demoiselles D'Avignon by Pablo Picasso Essay Example | Topics and Well Written Essays - 1500 words

Demoiselles D'Avignon by Pablo Picasso - Essay Example The essay "Demoiselles D'Avignon by Pablo Picasso" explores one of the most important pieces of art by Pablo Picasso. He completed the picture in 1907. Picasso always applied oil on his canvas. Presently, the picture is displayed in New York’s Museum of Modern Art. In the twentieth century, one of the most significant canvases, Picasso’s , Les Demoiselles D’Avignon, was created due to various reasons. First, among them was the confrontation he had with CÃ ©zanne’s extraordinary accomplishment at the posthumous show which took place in Paris in 1907, a year following the artist’s death. The retrospective exhibition drove the young Picasso, Matisse, as well as many other artists into competing with the inferences of the art of CÃ ©zanne. 1906’s Bonheur de Vivre by Matisse was his first attempt, which was later given to Leo & Gertrude Stein, who went ahead to hang it inside their living room thereby ensuring that all of the avant-garde artists and writers were capable of seeing and praising it. The praises led to the fulfillment of the promise made by CÃ ©zanne that the painting was worth them. Throughout his paintings, Picasso treated women the same way he treated his projects since he used to sketch a little, paint and then progress to the next painting. Although Picasso had over 25,000 works by his name, which mostly concentrated on women; to him, women were merely an object of his enjoyment and pleasure. According to Picasso, there are two sorts of women; the goddesses and the door mats.

Position Paper in Support of Patient Affordable Care Act Essay

Position Paper in Support of Patient Affordable Care Act - Essay Example This population lives each day not sure what would happen if they fell sick or were in need of medical attention. The absence of a medical insurance therefore means that they cannot visit the physician for regular check ups and will always postpone illnesses or trips to the doctor because they simply cannot afford it. Delayed medical care for fear of expenses is a disaster considering the number of people in the country and the illnesses that could be treated early turning fatal. People without health insurance are at the greatest risk of not catching illnesses early enough and not acquiring medical attention when need arises. This leads to an increase in healthcare premiums because of unpaid emergency medical bills of uninsured people (Gruber 33). In early 2010, president Obama signed the Affordable Care Act as a step to address the pending disaster of healthcare. This law was set in motion with comprehensive healthcare insurance reforms to deal with the healthcare issue of the Amer icans. According to young invincible, implementing the Act will carter for five major areas namely the extension of the dependent coverage to up to 26years, reforms for college heath plan and exchanges to be more established (Younginvincible.org). It will also offer a catastrophic plan for young adults and expand the Medicaid to the low-income adults who are childless. This plan will go to immense lengths in ensuring that every young person is insured or has access to healthcare through their parents plan. Overt he next few years, there ought to be no barriers when accessing medical care with the implementation of the Affordable care act. It is projected that by the year 2014, changes like a 50% discount on all brand name drugs, tax credits on small business, insurance plans for pre-existing medical conditions as well as an expansion on young adult coverage will be visible. Some of the plans are already underway (Pipes 52). Health systems implemented in other countries around the wo rld have proved to work effectively ensuring that almost every individual in that country is covered medically. According to sick around the world, a country like the United Kingdom has a National Health System (NHS) that is funded through taxes and is run by the government. It ensures that each person born in the U.K will have access and use the NHS (pbs.org). In addition, no one is presented with a medical bill through out the duration they are seeking medication. The initiative of the NHS has also reduced the waiting times that were previously required for elective surgeries. In a country like Japan which holds pride for the best health according to global statistics and the second largest economy. These people also visit the doctor thrice as much as Americans, use more drugs, have double the number of MRI scans, and reportedly spend more days in hospitals (pbs.org). Apparently, they spend only about half of what the United States spends per capita on healthcare. To achieve this, the Japanese have put it in law that every person must buy a health insurance plan through a community plan or through an employer. Reid then tours a country, which came up with the concept of national healthcare systems, Germany. Germany offers universal medical care, which includes mental health, dental, homeopathy, medical, and spa treatment for its 80 million people (pbs.org). They have devised a structure where the poor are paid for by the rich and the healthy

UK Budget Hotel Sector Essay Example | Topics and Well Written Essays - 2000 words

UK Budget Hotel Sector - Essay Example The importance of conducting this research is seen in the relevance of discussing financial crisis in today's time, which affects almost all businesses, sectors, and industries. In the light of this financial crisis, the study shall look at the direction and future of the UK budget hotel sector. The economic theories will help direct the research in its determination of the future of the sector in order to produce a socially scientific prediction on the direction of its future. The research is also relevant in today's era of globalization, which allows businesses to compete at a wider scope of markets. The financial crisis in which the UK budget hotel is situated is also a relevant point of discussion since it enables for a development of insights on the current global crisis situation. Hence, since globalisation, competitive advantage, and economic productivity are relevant concepts in today's businesses, the pursuit for this research makes it an important endeavour. Likewise, the current global crisis that puts nations, trade, and businesses in a rather bad condition is an important aspect that will be necessarily touched in the research due to the topic itself. All of these considerations will be tackled in the research, making it fit to the body of knowledge which other researchers may utilise for their own. IV. Literature Review The literature review will comprise of three parts: The development of the UK budget hotel sector The globalised industry in which the budget hotel sector is situated How financial crisis affect budget hotels The Development of the UK Budget Hotel Sector Brotherton (2004) explores the critical success factors in the operations of UK budget hotel and utilises the questionnaire survey design in ascertaining the relevance of these factors in academic and trade literature. A report from Hall (2004) suggests that in over a five-year period from 1997, there was an annual growth rate of almost 20 percent in room capacity among the UK budget hotel sector. The report likewise examines key emerging trends in the sector, including the branded budget hotels' city-centre focus. In the development of UK budget hotel, it is important to mention that the management of "commitment cultures," the recruitment and selection procedures, and the training and development practices, which are all in the heart of human resource management (HRM) are important points to ponder (McGunnigle and Jameson, 2000, p. 404). It is suggested that firms that adopt an HRM approach put high regard on employee commitment, sophisticated and objective

SLP - WORK MOTIVATION Essay Example | Topics and Well Written Essays - 500 words

SLP - WORK MOTIVATION - Essay Example In acquiring addition skills in training, I have applied them in my work place to make it more presentable. When encountering some hardships and problems, I always consult my boss regularly regarding any troubling issues though not all the time he is ready with an answer. Being inventive with some ideas to which I share with my boss before tackling my job, has contributed to the current success. Regular meetings with him aimed at discussing as well as highlighting how I can improve my working skills has also played a significant role, which aligns with my scores so far obtained. Based on the content and figures above depicting my commitment and the freedom I enjoy at my work place, I believe, if my employer starts giving rewards and appraisals to employees, this score would rapidly improve. For instance, incentives like new promotions opportunities if one achieves a certain goal set by the employer. This will motivate a healthy competition among employees to vie for the new positions though in terms of outstanding respective performances (McGregor). Another aspect encompasses if the employer regularly increases employees’ based on merit, this will motivate one to work extra hard and do a presentable job accordingly. This is especially in introducing overtime remunerations for extra worked hours will encourage employees to work even hard. Praising and recommending employees work will motivate and encourages one to keep on working hard within a working institution. Management should involve employees in decision making by listening to their suggestions about what they feel and think (Chapman, 2014). This will be a great privilege towards making employees feel honored and thought of positively by their superiors. If the employer comes up with a plan to pay for extra training for employees to acquire additional skills to improve, their work quality I strongly believe this can improve the personal score of an

Annotated Outline and Bibliography Assignment Example | Topics and Well Written Essays - 1250 words

Annotated Outline and Bibliography - Assignment Example In the military, leaders are in place to train new leaders and in business the means for teaching leadership is not different. As the Chief Executives within an organization, their influence is something that people look up to for guide on how the daily operation should run. Influence is the active relationship among people; however, also inherent in this definition is the concept that influence is multidirectional and noncoercive (Draft and Lane, 2008). A governing board is put together to run as a unit in order to get the job done, but the current means of getting that done is illustrated through the leadership on the board. The means of how one leads can also become a problem, especially if that management style is one that micro manages employees. Communication plays a pivotal part when examining quality issues within an organization. In regards to communication, the lack of proper channels to relay information is one of many problems within RHC. Current leadership lacks the skill especially to professionally transmit verbal communication. This book characterizes a number of the finest methods, organization, and outcomes for various key areas of management in a healthcare organisation. According to the author, the manager has to apply a number of processes and designs to ensure quality in the organisation. These include open systems, community-focused strategic management, and continuous improvement are discussed along with issues such as personal and public health, patient motivations, and safe, effective, efficient patient care. The governing board is important based on its mission and vision, budgeting, quality, membership, board performance, compensation, effectiveness, and legal issues regarding board membership and authority. Basing on the decision theory used to constitute a clinical quality improvement model, RHC may implement protocols to improve the quality of healthcare in accordance with realistic

Internal and external environment Essay Example for Free

Internal and external environment Essay Introduction Internal and external environment of each company is a concept of poles apart. The knowledge of human is influenced by various factors that are surrounding the environment in which that an individual is placed. A continuous and steady improvement is the order of the day for increasing the human efficiency in working environment. â€Å"THE modern business man is the true heir of the old magicians. Every thing he touches seems to increase ten or a hundredfold in value and usefulness. All the old methods, old tools, old instruments have yielded to his transforming spell or else been discarded for new and more effective substitutes. In a thousand industries the profits of to-day are wrung from the wastes or unconsidered trifles of yesterday†(Scott, Walter Dill, 1998 Increasing Human Efficiency in Business, Chap. I. pg. 1) The era of computerization is system based approach at every level of working, whether it is in business, management, information technology or any industrial and social sector. The adherence to system has been fruitful in all aspects and also in locating the risk areas that can be monitored to avoid such risks with appropriate standards of management techniques and tools. Definition of system and Manager’s adoption of principles of system A system is defined as an organized, unitary whole composed of two or more interdependent parts (subsystems) where the whole contains identifiable boundaries from its environment (suprasystem). The practice of system is based on system principles and methods which are to be understood by a manager are : (1) Define company as a system (2) Establish system objectives (performance criteria) (3) Identify wider systems (environment). (4) Create formal subsystems (including a humanistic, psychosocial subsystem (5) Integrate the subsystems with the whole system (if not the subsystems themselves, whatever interrelates them with other subsystems. There are various aspects that are co-related with systems approach in terms of management of external and internal environment and how management theory is applicable in legal matters and what is the status of manager in communication in solving complex issues that arise from time to time in both external and internal environment. This is another way of stating that a manager has to be dynamically competitive and work advantageously in both environments with the prop of system theory. Systems theory as prescribed above, requires a complete in-depth understanding about working of a company apart from day to day analysis of performance within and outside environment of a company. The tools that are effective in measuring and managing the affairs of a company are viz., time management, risk management, supply chain management, team management, customer relation management, operation management, management of information systems, decision supportive systems and organizational behavior. A continuous persisting efforts of a manager produces emergence of new ideas and strategies apart from assisting in identifying key areas of a problem. It can also be stated that problems produce some of the best systematic ideas that are recognized as best strategies in the long term for the benefit and growth of a company. †And while the body is confined to one planet, along which it creeps with pain and difficulty; the thought can in an instant transport us into the most distant regions of the universe; or even beyond the universe, into the unbounded chaos, where nature is supposed to lie in total confusion. What never was seen, or heard of, may yet be conceived; nor is any thing beyond the power of thought, except what implies an absolute contradiction†. â€Å"But though our thought seems to possess this unbounded liberty, we shall find, upon a nearer examination, that it is really confined within very narrow limits, and that all this creative power of the mind amounts to no more than the faculty of compounding, transposing, augmenting, or diminishing the materials afforded us by the senses and experience†(Raleigh, N. C Alex Catalogue, An Enquiry concerning Human understanding, Sec. II. The origin of ideas, pg. 11) Ideas are the final output of thinking process, which has to undergo a brain storming session, group discussion and after several workshops, a company launches a new product.

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,