Pharmacogenetics
Pharmacogenetics
Definition
Pharmacogenetics is the study of how the actions of and reactions to drugs vary with the patient's genes.
Description
Genes are the portions of chromosomes that determine many of the traits in every living thing. In humans, genes influence race, hair and eye color, gender, height, weight, aspects of behavior, and even the likelihood of developing certain diseases. Although some traits are a combination of genetics and environment, researchers are still discovering new ways in which people are affected by their genes.
Pharmacogenetics is the study of how people respond to drug therapy. Although this science is still new, there have been many useful discoveries. It has long been known that genes influence the risk of developing certain diseases, or that genes could determine traits such as hair and eye color. Genes can also alter the risk of developing different diseases. It has long been known that people of African descent were more likely to have sickle cell anemia than people of other races. People of Armenian, Arab, and Turkish heritage are more prone to familiar Mediterranean fever than people of other nationalities. More recently, discoveries have shown that genes can determine other aspects of each individual, down to the level of the enzymes produced in the liver. Since these enzymes determine how quickly a drug is removed from the body, they can make major differences in the way people respond to drugs. Some of the most basic work concerns the way race and gender influence drug reactions—and race and gender are genetically determined.
Women often respond differently than men to drugs at the same dose levels. For example, women are more likely to have a good response to the antidepressant drugs that act as serotonin specific reuptake inhibitors (SSRIs, the group that includes Prozac and Paxil) than they are to the older group of tricyclic antidepressants (the group that includes Elavil and Tofranil). Women have a greater response to some narcotic pain reliving drugs than do men, but get less relief from some non-narcotic pain medications. Women may show a greater response to some steroid hormones than men do, but have a lower level of response to some anti-anxiety medications than men.
Race may also affect the way people respond to some medications. In this case, race implies specific genetic factors that are generally, but not always, found among members of specific ethnic groups. For example, the angiotensin II inhibitor enalopril (Vasotec), which is used to lower blood pressure, works better in Caucasians than in Blacks. Carvedilol (Coreg), a beta-adrenergic blocking agent that is also used to lower blood pressure, is more effective than other drugs in the same class when used to treat Black patients. Black patients with heart failure appear to respond better to a combination of hydralazine and isosorbide than do Caucasian patients using the same medication.
More specific research has identified individual genes than may influence drugs response, without relying on group information such as gender and race. Specific genes have been identified that may determine how patients will respond to specific drugs. For example, some genes may determine whether people will get pain relief from codeine, or how well they will respond to drugs used to treat cancer.
Causes and symptoms
Genes alter responses to drugs because the genes influence many parts of the body iteself. One of the simplest examples is the gene that influences body weight. Since many drugs are soluble in body fat, people with large amounts of fat will have these drug deposited into their fat stores. This means that there are lower levels of the drug that can reach the actual organs on which they work.
In the case of gender responses to antidepressants, women show greater response to serotonin specific antidepressants because women naturally have lower levels of serotonin than men do. This makes women more likely to develop a type of depression marked by low serotonin levels, but it also means that women will respond better to replacement of serotonin.
Because people of the same race carry similar genes, studies based on race were the earliest types of pharmacogenetic studies. One study evaluated the levels of alcohol dehydrogenase in people of different nationalities. This is an enzyme involved in the metabolism of alcohol. When people with high levels of this enzyme, or people in whom the enzyme acts more rapidly than in other people, drink alcohol, they are subject to facial flushing and slowing of the heartbeat. The activity of this enzyme is determined by genetics, and different levels can be seen in different races because these people belong to the same gene pools. Among Asiatic people, 85% have high levels of this enzyme, compared to 20% of Swiss people, and only 5-10% of British people.
Another trait that is influenced by genes is a liver enzyme, CYP2D6. This enzyme metabolizes some drugs, convert them to a form that can be removed from the body. Genes determine the level of this enzyme in the liver. People with low levels of CYP2D6 will metabolize drugs slowly. Slow metabolism means the drugs will act for a longer period of time. Slow metabolizers reaspond to smaller doses of medications that are eliminated by this enzyme, while fast metabolizers, people who have a lot of the enzyme, will need larger drug doses to get the same effects. At the same time, low levels of CYP2D6 means that people taking the drugs that are metabolized by this enzyme will have higher drug levels, and are more likely to have unwanted side effects.
Another enzyme that can be important in drug dosing is called 2C9, and this enzyme is responsible for metabolizing the anticoagulant drug warfarin (Coumadin). Most people take warfarin in a dose of about 5 milligrams a day, but people who have low levels of 2C9 normally require a dose of only 1-5 milligrams a week.
Yet another mechanism of drug activity is the presence or absence of a specific drug receptor site. Drugs act by binding to specific chemicals, receptor sites, within body cells. Genes may help determine how many of these cells there are. The action of the widely used antipsychotic drug haloperidol (Haldol) depends on its ability to bind to the dopamine (D2) receptor site. The number of these sites are determined by genetics. In one study, 63% of patients whose genes caused a large number of these receptor sites had a response to treatment with haloperidol, while only about 29% of patients with a smaller number of dopamine (D2) receptor sites did well on the drug.
Other genetic studies indicate that genes may affect how people respond to foods as well as to drugs. An Australian study of osteoporosis (softening of the bones that often occurs in elderly people), reported that separate genes may affect response to vitamin D, calcium, and estrogens.
Implications
Although the study is still new, pharmacogenetics promises to offer great benefits in drug effectiveness and safety.
At the present time, most drug treatment is done by trial and error. Physicians prescribe medication, and the patient tries the drug. The drug may work, or it may not. It may cause adverse effects, or it may be safe. If the drug does not work, the dose is increased. If it causes harmful or unpleasant effects, a new drug is tried until, finally, the right drug is found. In some cases this procedure may take weeks or even months.
In other cases, drugs are carefully tested, and appear to be safe and effective. Only after they are approved for general use are reports of serious adverse effects that did not appear in the initial studies documented. This can occur if there is a rare gene that affects the way in which the drug acts, or the way in which the drug is metabolized.
With increasing understanding of how genes determine the way people respond to drugs, it will be possible to select drugs and doses based on a greater understanding of each individual patient. This promises more effective drug therapy, with greater safety and fewer treatment failures.
Physicians may be able to compare the person's genetic make-up with the properties of specific drugs, and make informed decisions about which drug in a group will work most effectively or most safely.
Resources
BOOKS
From Genome to Therapy: Integrating New Technologies with Drug Development. New York: John Wiley, 2000.
PERIODICALS
"A DNA tragedy." Fortune October 30, 2000. "Screening for genes." Newsweek February 8, 1999.
ORGANIZATIONS
National Institute of General Medical Sciences. Division of Pharmacology, Physiology, and Biological Chemistry. 45 Center Dr., MSC 6200 Bethesda, MD 20892-6200.
University of California, Los Angeles Harbor-UCLA Medical Center Research and Education Institute 1124 W Carson St., B-4 South Torrance, CA 90502.
KEY TERMS
Enzyme— Proteins produced by living cells that help produce specific biochemical reactions in the body.
Metabolism— The process by which foods and drugs are broken down for use and removal from the body.
Sickle cell anemia— A severe, inheritable disease, most common among people of African descent, marked by deformation and destruction of red blood cells, and by adherence of blood cells to the walls of blood vessels.
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics is the exploration of the relationship between inherited genes and the ability of the body to metabolize drugs. Although research interests are rapidly expanding, by early 2003 pharmacogenetics research concentrated on trying establish connections between the genes carried by an individual (genotype) and specific reactions to drugs (e.g., side effects, toxicities, etc.).
Modern medicine relies on the use of therapeutic drugs to treat disease , but one of the longstanding problems has been the documented variation in patient response to drug therapy. The recommended dosage is usually established at a level shown to be effective in 50% of a test population, and based on the patient's initial response, the dosage may be increased, decreased, or discontinued. In rare situations, the patient may experience an adverse reaction to the drug and be shown to have a pharmacogenetic disorder. The unique feature of this group of diseases is that the problem does not occur until after the drug is given, so a person may have a pharmacogenetic defect and never know it if the specific drug required to trigger the reaction is never administered.
For example, consider the case of a 35-year-old male who is scheduled for surgical repair of a hernia . The patient is otherwise in excellent health and has no family history of any serious medical problems. After entering the operating theater, an inhalation anesthetic and/or muscle relaxant is administered to render the patient unconscious. Unexpectedly, there is a significant increase in body temperature , and the patient experiences sustained muscle contraction. If this condition is not reversed promptly, it can lead to death. Anesthesiologists are now familiar with this type of reaction. It occurs only rarely, but it uniquely identifies the patient as having malignant hyperthermia, a rare genetic disorder that affects the body's ability to respond normally to anesthetics. Once diagnosed with malignant hyperthermia, it is quite easy to avoid future episodes by simply using a different type of anesthetic when surgery is necessary, but it often takes one negative, and potentially life threatening, experience to know the condition exists.
An incident that occurred in the 1950s further shows the diversity of pharmacogenetic disorders. During the Korean War, service personnel were deployed in a region of the world where they were at increased risk for malaria . To reduce the likelihood of acquiring that disease, the antimalarial drug primaquine was administered. Shortly thereafter, approximately 10% of the African-American servicemen were diagnosed with acute anemia and a smaller percentage of soldiers of Mediterranean ancestry showed a more severe hemolytic anemia. Investigation revealed that the affected individuals had a mutation in the glucose 6-phosphate dehydrogenase (G6PD) gene . Functional G6PD is important in the maintenance of a balance between oxidized and reduced molecules in the cells, and, under normal circumstances, a mutation that eliminates the normal enzyme function can be compensated for by other cellular processes. However, mutation carriers are compromised when their cells are stressed, such as when the primaquine is administered. The system becomes overloaded, and the result is oxidative damage of the red blood cells and anemia. Clearly, both the medics who administered the primaquine and the men who took the drug were unaware of the potential consequences. Fortunately, once the drug treatment was discontinued, the individuals recovered.
Drugs are essential to modern medical practice, but, as in the cases of malignant hyperthermia and G6PD deficiency, it has become clear that not all individuals respond equally to each drug. Reactions can vary from positive improvement in the quality of life to life threatening episodes. Annually, in the United States, there are over two million reported cases of adverse drug reactions and a further 100,000 deaths per year because of drug treatments. The Human Genome Project and other research endeavors provided, and continue to provide, information that is allowing a better understanding of the underlying causes of pharmacogenetic anomalies with the hope that eventually the number of negative episodes can be reduced.
In particular, research on one enzyme family is beginning to revolutionize the concepts of drug therapy. The cytochrome P450 system is a group of related enzymes that are key components in the metabolic conversion of over 50% of all currently used drugs. Studies involving one member of this family, CYP2D6, have revealed the presence of several polymorphic genetic variations (poor, intermediate, extensive, and ultra) that result in different clinical phenotypes with respect to drug metabolism . For example, a poor metabolizer has difficulty in converting the therapeutic drug into a useable form, so the unmodified chemical will accumulate in the body and may cause a toxic overdose. To prevent this from happening, the prescribed dosage of the drug must be reduced. An ultra metabolizer, on the other hand, shows exceedingly rapid breakdown of the drug to the point that the substance may be destroyed so quickly that therapeutic levels may not be reached, and the patient may therefore never show any benefit from treatment. In these cases, switching to another type of drug that is not associated with CYP2D6 metabolism may prove more beneficial. The third phenotypic class, the extensive metabolizers, is less extreme than the ultra metabolism category, but nevertheless presents a relatively rapid turnover of drug that may require a higher than normal dosage to maintain a proper level within the cells. And, finally, the intermediate phenotype falls between the poor and extensive categories and gives reasonable metabolism and turnover of the drug. This is the group for whom most recommended drug dosages appear to be appropriate. However, the elucidation of the four different metabolic classes has clearly shown that the usual "one size fits all" recommended drug dose is not appropriate for all individuals. In the future, it will become increasingly necessary to know the patient's metabolic phenotype with respect to the drug being given to determine the most appropriate regimen of therapy for that individual.
At the present time, pharmacogenetics is still in its infancy with its full potential yet to be realized. Based on current studies, it is possible to envision many different applications in the future. In addition to providing patient specific drug therapies, pharmacogenetics will aid in the clinician's ability to predict adverse reactions before they occur and identify the potential for drug addiction or overdose. New tests will be developed to monitor the effects of drugs, and new medications will be found that will specifically target a particular genetic defect. Increased knowledge in this field should provide a better understanding of the metabolic effects of food additives, work related chemicals, and industrial byproducts. In time, these advances will improve the practice of medicine and become the standard of care.
See also Chromosome mapping; Genetic engineering; Genotype and phenotype; Molecular biology.
Resources
books
Brooker, R. Genetics Analysis and Principals Menlo Park: Benjamin Cummings, 1999.
Glick, B.R., and J. J. Pasternak. Molecular Biotechnology,Principles and Applications of recombinant DNA. 2nd ed. Washington: American Society of Microbiology Press, 1998.
Jorde, L.B., J. C. Carey, M. J. Bamshad, and R. L. White. Medical Genetics. 2nd ed. St. Louis: Mosby-Year Book, Inc., 2000.
periodicals
Chakravarti, A. "To a Future of Genetic Medicine" Nature 409 (2001): 822–823.
Stein, C.M.; Chim C. Lang; Hong-Guang Xie; et. al. "Hypertension in Black People: Study of Specific Genotypes and Phenotypes Will Provide a Greater Understanding of Interindividual and Interethnic Variability in Blood Pressure Regulation than Studies Based On Race." Pharmacogenetics 11 (2001): 95-110
Connie Stein
Pharmacogenetics
Pharmacogenetics
Definition
Pharmacogenetics is one of the newest subspecialties of genetics that deals with the relationship between inherited genes and the ability of the body to metabolize drugs.
Description
Medicine today relies on the use of therapeutic drugs to treat disease, but one of the longstanding problems has been the documented variation in patient response to drug therapy. The "recommended" dosage is usually established at a level shown to be effective in 50% of a test population, and based on the patient's initial response, the dosage may be increased, decreased, or discontinued. In rare situations, the patient may experience an adverse reaction to the drug and be shown to have a pharmacogenetic disorder. The unique feature of this group of diseases is that the problem does not occur until after the drug is given, so a person may have a pharmacogenetic defect and never know it if the specific drug required to trigger the reaction is never administered.
Adverse reactions
Consider the case of a 35-year-old male who is scheduled for surgical repair of a hernia. The patient is otherwise in excellent health and has no family history of any serious medical problems. After entering the operating theater, an inhalation anesthetic and/or muscle relaxant is administered to render the patient unconscious. Unexpectedly, there is a significant increase in body temperature, and the patient experiences sustained muscle contraction. If this condition is not reversed promptly, it can lead to death. Anesthesiologists are now very familiar with this type of reaction. It occurs only rarely, but it uniquely identifies the patient as having malignant hyperthermia , a rare autosomal dominant disorder that affects the body's ability to respond normally to anesthetics. Once diagnosed with malignant hyperthermia, it is quite easy to avoid future episodes by simply using a different type of anesthetic when surgery is necessary, but it often takes one negative, and potentially life-threatening, experience to know the condition exists.
An incident that occurred in the 1950s further shows the diversity of pharmacogenetic disorders. During the Korean War, service personnel were deployed in a region of the world where they were at increased risk for malaria. To reduce the likelihood of acquiring that disease, the antimalarial drug primaquine was administered prophylactically. Shortly thereafter, approximately 10% of the African-American servicemen were diagnosed with acute anemia and a smaller percentage of soldiers of Mediterranean ancestry showed a more severe hemolytic anemia. Investigation revealed that the affected individuals had a mutation in the glucose 6-phosphate dehydrogenase (G6PD) gene . Functional G6PD is important in the maintenance of a balance between oxidized and reduced molecules in the cells, and, under normal circumstances, a mutation that eliminates the normal enzyme function can be compensated for by other cellular processes. However, mutation carriers are compromised when their cells are stressed, such as when the primaquine is administered. The system becomes overloaded, and the result is oxidative damage of the red blood cells and anemia. Clearly, both the medics who administered the primaquine and the men who took the drug were unaware of the potential consequences. Fortunately, once the drug treatment was discontinued, the individuals recovered.
Research efforts
Drugs are essential to modern medical practice, but, as in the cases of malignant hyperthermia and G6PD deficiency, it has become clear that not all individuals respond equally to each drug. Reactions can vary from positive improvement in the quality of life to life threatening episodes. Annually, in the United States, there are over two million reported cases of adverse drug reactions and a further 100,000 deaths per year as a result of drug treatments. The Human Genome Project and other research endeavors are now providing information that is allowing a better understanding of the underlying causes of pharmacogenetic anomalies with the hope that eventually the number of negative episodes can be reduced.
In particular, research on one enzyme family is beginning to revolutionize the concepts of drug therapy. The cytochrome P450 system is a group of related enzymes that are key components in the metabolic conversion of over 50% of all currently used drugs. Studies involving one member of this family, CYP2D6, have revealed the presence of several polymorphic genetic variations (poor, intermediate, extensive, and ultra) that result in different clinical phenotypes with respect to drug metabolism. For example, a poor metabolizer has difficulty converting the therapeutic drug into a useable form, so the unmodified chemical will accumulate in the body and may cause a toxic overdose. To prevent this from happening, the prescribed dosage of the drug must be reduced.
An ultra metabolizer, on the other hand, shows exceedingly rapid breakdown of the drug to the point that the substance may be destroyed so quickly that therapeutic levels may not be reached, and the patient may therefore never show any benefit from treatment. In these cases, switching to another type of drug that is not associated with CYP2D6 metabolism may prove more beneficial.
The third phenotypic class, the extensive metabolizers, is less extreme than the ultra metabolism category, but nevertheless presents a relatively rapid turnover of drug that may require a higher than normal dosage to maintain a proper level within the cells. And, finally, the intermediate phenotype falls between the poor and extensive categories and gives reasonable metabolism and turnover of the drug. This is the group for whom most "recommended" drug dosages appear to be appropriate.
However, the elucidation of the four different metabolic classes has clearly shown that the usual "one size fits all" recommended drug dose is not appropriate for all individuals. In the future, it will become increasingly necessary to know the patient's metabolic phenotype with respect to the drug being given to determine the most appropriate regimen of therapy for that individual.
Future applications
At the present time, pharmacogenetics is still in its infancy with its full potential yet to be realized. Based on current studies, it is possible to envision many different applications in the future. In addition to providing patient specific drug therapies, pharmacogenetics will aid in the clinician's ability to predict adverse reactions before they occur and identify the potential for drug addiction or overdose. New tests will be developed to monitor the effects of drugs, and new medications will be found that will specifically target a particular genetic abnormality. Increased knowledge in this field should provide a better understanding of the metabolic effects of food additives, work related chemicals, and industrial by–products. In time, these advances will improve the practice of medicine and become the standard of care.
Constance K. Stein, PhD
Pharmacogenetics
Pharmacogenetics
Definition
Pharmacogenetics is one of the newest subspecialties of genetics that deals with the relationship between inherited genes and the ability of the body to metabolize drugs.
Description
Medicine today relies on the use of therapeutic drugs to treat disease, but one of the longstanding problems has been the documented variation in patient response to drug therapy. The "recommended" dosage is usually established at a level shown to be effective in 50% of a test population, and based on the patient's initial response, the dosage may be increased, decreased, or discontinued. In rare situations, the patient may experience an adverse reaction to the drug and be shown to have a pharmacogenetic disorder. The unique feature of this group of diseases is that the problem does not occur until after the drug is given, so a person may have a pharmacogenetic defect and never know it if the specific drug required to trigger the reaction is never administered.
Adverse reactions
Consider the case of a 35-year-old male who is scheduled for surgical repair of a hernia. The patient is otherwise in excellent health and has no family history of any serious medical problems. After entering the operating theater, an inhalation anesthetic and/or muscle relaxant is administered to render the patient unconscious. Unexpectedly, there is a significant increase in body temperature, and the patient experiences sustained muscle contraction. If this condition is not reversed promptly, it can lead to death. Anesthesiologists are now very familiar with this type of reaction. It occurs only rarely, but it uniquely identifies the patient as having malignant hyperthermia , a rare autosomal dominant disorder that affects the body's ability to respond normally to anesthetics. Once diagnosed with malignant hyperthermia, it is quite easy to avoid future episodes by simply using a different type of anesthetic when surgery is necessary, but it often takes one negative, and potentially life-threatening, experience to know the condition exists.
An incident that occurred in the 1950s further shows the diversity of pharmacogenetic disorders. During the Korean War, service personnel were deployed in a region of the world where they were at increased risk for malaria. To reduce the likelihood of acquiring that disease, the antimalarial drug primaquine was administered prophylactically. Shortly thereafter, approximately 10% of the African-American servicemen were diagnosed with acute anemia and a smaller percentage of soldiers of Mediterranean ancestry showed a more severe hemolytic anemia. Investigation revealed that the affected individuals had a mutation in the glucose 6-phosphate dehydrogenase (G6PD) gene . Functional G6PD is important in the maintenance of a balance between oxidized and reduced molecules in the cells, and, under normal circumstances, a mutation that eliminates the normal enzyme function can be compensated for by other cellular processes. However, mutation carriers are compromised when their cells are stressed, such as when the primaquine is administered. The system becomes over-loaded, and the result is oxidative damage of the red blood cells and anemia. Clearly, both the medics who administered the primaquine and the men who took the drug were unaware of the potential consequences. Fortunately, once the drug treatment was discontinued, the individuals recovered.
Research efforts
Drugs are essential to modern medical practice, but, as in the cases of malignant hyperthermia and G6PD deficiency, it has become clear that not all individuals respond equally to each drug. Reactions can vary from positive improvement in the quality of life to life threatening episodes. Annually, in the United States, there are over two million reported cases of adverse drug reactions and a further 100,000 deaths per year as a result of drug treatments. The Human Genome Project and other research endeavors are now providing information that is allowing a better understanding of the underlying causes of pharmacogenetic anomalies with the hope that eventually the number of negative episodes can be reduced.
In particular, research on one enzyme family is beginning to revolutionize the concepts of drug therapy. The cytochrome P450 system is a group of related enzymes that are key components in the metabolic conversion of over 50% of all currently used drugs. Studies involving one member of this family, CYP2D6, have revealed the presence of several polymorphic genetic variations (poor, intermediate, extensive, and ultra) that result in different clinical phenotypes with respect to drug metabolism. For example, a poor metabolizer has difficulty converting the therapeutic drug into a useable form, so the unmodified chemical will accumulate in the body and may cause a toxic overdose. To prevent this from happening, the prescribed dosage of the drug must be reduced.
An ultra metabolizer, on the other hand, shows exceedingly rapid breakdown of the drug to the point that the substance may be destroyed so quickly that therapeutic levels may not be reached, and the patient may therefore never show any benefit from treatment. In these cases, switching to another type of drug that is not associated with CYP2D6 metabolism may prove more beneficial.
The third phenotypic class, the extensive metabolizers, is less extreme than the ultra metabolism category, but nevertheless presents a relatively rapid turnover of drug that may require a higher than normal dosage to maintain a proper level within the cells. And, finally, the intermediate phenotype falls between the poor and extensive categories and gives reasonable metabolism and turnover of the drug. This is the group for whom most "recommended" drug dosages appear to be appropriate.
However, the elucidation of the four different metabolic classes has clearly shown that the usual "one size fits all" recommended drug dose is not appropriate for all individuals. In the future, it will become increasingly necessary to know the patient's metabolic phenotype with respect to the drug being given to determine the most appropriate regimen of therapy for that individual.
Future applications
At the present time, pharmacogenetics is still in its infancy with its full potential yet to be realized. Based on current studies, it is possible to envision many different applications in the future. In addition to providing patient-specific drug therapies, pharmacogenetics will aid in the clinician's ability to predict adverse reactions before they occur and identify the potential for drug addiction or overdose. New tests will be developed to monitor the effects of drugs, and new medications will be found that will specifically target a particular genetic abnormality. Increased knowledge in this field should provide a better understanding of the metabolic effects of food additives, work related chemicals, and industrial byproducts. In time, these advances will improve the practice of medicine and become the standard of care.
Constance K. Stein, PhD
Pharmacogenetics
Pharmacogenetics
Pharmacogenetics refers to the study of the relationship between inherited genes and the ability of the body to metabolize drugs. Specifically, pharmacogenetics focuses on the connections between the genes carried by an individual (genotype) and specific reactions to drugs such as side effects and toxicity.
Modern medicine relies on the use of therapeutic drugs to treat disease, but one of the longstanding problems has been the documented variation in patient response to drug therapy. The recommended dosage is usually established at a level shown to be effective in 50% of a test population, and based on the patient’s initial response, the dosage may be increased, decreased, or discontinued. In rare situations, the patient may experience an adverse reaction to the drug and be shown to have a pharmacogenetic disorder. The unique feature of this group of diseases is that the problem does not occur until after the drug is given, so a person may have a pharmacogenetic defect and never know it if the specific drug required to trigger the reaction is never administered.
As a historical example, during the Korean War (1950-1953), service personnel were deployed in a region of the world where they were at increased risk for malaria. To reduce the likelihood of acquiring that disease, the antimalarial drug primaquine was administered. Shortly thereafter, approximately 10% of the African-American servicemen were diagnosed with acute anemia and a smaller percentage of soldiers of Mediterranean ancestry showed a more severe hemolytic anemia. Investigation revealed that the affected individuals had a mutation in the gene that codes for an enzyme called glucose 6-phosphate dehydrogenase (G6PD). Functional G6PD is important in the maintenance of the proper balance of certain molecules in cells. Usually, a mutation that eliminates the normal enzyme function can be compensated for by other cellular processes. However, people with a G6PD gene mutation experience difficulty when their cells are stressed such as when the primaquine is administered. The system becomes overloaded, and the result is oxidative damage of the red blood cells and anemia. Clearly, both the medics who administered the prima-quine and the men who took the drug were unaware of the potential consequences. Fortunately, once the drug treatment was discontinued, the individuals recovered.
Drugs are essential to modern medical practice, but, as in the cases of malignant hyperthermia and G6PD deficiency, it has become clear that not all individuals respond equally to each drug. Reactions can vary from positive improvement in the quality of life to life threatening episodes. Over 2 million reported cases of adverse drug reactions occur each year in the United States and a further 100,000 deaths per year because of drug treatments.
In particular, research on one enzyme family is beginning to revolutionize the concepts of drug therapy. The cytochrome P450 system is a group of related enzymes that are key components in the metabolic conversion of over 50% of all currently used drugs. Studies involving one member of this family, CYP2D6, have revealed the presence of several polymorphic genetic variations (poor, intermediate, extensive, and ultra) that result in different clinical phenotypes with respect to drug metabolism. For example, a poor metabolizer has difficulty in converting the therapeutic drug into a useable form, so the unmodified chemical will accumulate in the body and may cause a toxic overdose. To prevent this from happening, the prescribed dosage of the drug must be reduced. An ultra metabolizer, on the other hand, shows exceedingly rapid breakdown of the drug to the point that the substance may be destroyed so quickly that therapeutic levels may not be reached, and the patient may therefore never show any benefit from treatment. In these cases, switching to another type of drug that is not associated with CYP2D6 metabolism can prove more beneficial. The third phenotypic class, the extensive metabolizers, is less extreme than the ultra metabolism category, but nevertheless presents a relatively rapid turnover of drug that may require a higher than normal dosage to maintain a proper level within the cells. Finally, the intermediate phenotype falls between the poor and extensive categories and gives reasonable metabolism and turnover of the drug. This is the group for whom most recommended drug dosages appear to be appropriate. These observations highlight that importance of pharmacogenetics; knowledge of a patient’s metabolic phenotype with respect to the drug can help determine the most appropriate regimen of therapy for that individual.
Resources
BOOKS
Hall, Ian P., and Munir Pirmohamed. Pharmacogenetics. London: Informa Healthcare, 2006.
Hedgecoe, Adam. The Politics of Personalised Medicine: Pharmacogenetics in the Clinic. Cambridge: Cambridge University Press, 2005.
Wilkins, Martin R. Cardiovascular Pharmacogenetics. New York: Springer, 2004.
Connie Stein