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.