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Pharmacogenetics and Pharmacogenomics

Molecular Interactions And Drug Effectiveness

Pharmacogenomics is a branch of pharmacogenetics, a science that deals with the heritable traits responsible for the individual differences in the ways people respond to drugs. It is remarkable, considering the myriad of medications we have today, how little we understand about how most of them actually work. There are many factors that influence the effectiveness of a particular drug, including how the drug enters the body's cells, how rapidly it is degraded by metabolic enzymes, and how it interacts with target molecules in the body, such as drug receptors.

Consider, for example, a common general anesthetic drug, called succinylcholine. In the 1950s doctors noticed that some patients suffered prolonged respiratory apnea (difficulty breathing) after being treated with succinylcholine. This syndrome was found to be caused by mutations in a gene for the enzyme butyrylcholinesterase. Normally butyrylcholinesterase in the blood degrades succinylcholine, and the anesthetic effects of the drug wear off with time. But in patients with mutations that inactivate or weaken butyrylcholinesterase, the anesthetic persists in the body, causing the dangerous side effect.

Cytochrome P450 is a member of a large family of enzymes that inactivate more than half of all drugs. There are many different alleles of cytochrome P450. Some alleles are very inefficient at inactivating drugs. In individuals with these alleles, termed "poor metabolizers," drugs can accumulate in the body to levels that produce toxic effects. In contrast, some people have extra copies of cytochrome P450 genes and produce excessive levels of the enzyme. In these individuals ("ultrarapid metabolizers"), drugs become inactivated so rapidly that they may not accumulate to the concentrations needed to be effective.

Adverse drug reactions such as the examples just discussed account for over one hundred thousand deaths each year in the United States. If a physician can determine the genotype of patients with respect to the genes that Stephen Liggett uses this cell harvester to perform research in his laboratory at the University of Cincinnati. Dr. Liggett works towards understanding better how genes and drugs interact. encode these proteins, then he or she may be able to prescribe the most appropriate dosage for a particular drug, or a better-suited drug.

A major obstacle, however, is that so many different proteins affect each drug. Some are well characterized, but most are completely unknown. This is where pharmacogenomics promises to revolutionize medicine. With the sequence of the entire human genome having been determined, and with the development of modern gene analysis technologies, scientists may now be able to pinpoint every gene that influences the effectiveness of any drug. Physicians would then be able to genotype their patients. For example, they could determine whether a patient has P450 alleles that make him a poor metabolizer or an ultrarapid metabolizer.

Not only can pharmacogenomics provide information about the best drug therapy for patients, but it can also be used to predict whether a person is predisposed to contracting a heritable disease. Mutant alleles of many genes have been shown to predispose people to diseases such as breast cancer, Alzheimer's disease, and Huntington's disease. If doctors can identify such mutant alleles in patients long before any sign of disease becomes apparent, they may be able to treat the disease better when it first appears or even prevent it before it strikes.

Of course, this powerful technology carries with it many ethical questions: If you carried a gene that gave you a moderate probability of eventually contracting a fatal disease, should you be told? What if there were no treatments for the disease? Who should have access to a patient's genetic information? If a health insurance company finds out that a person has a set of genes that predispose her to a disease that is costly to treat, should it be allowed to deny her insurance coverage?

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 3Pharmacogenetics and Pharmacogenomics - Molecular Interactions And Drug Effectiveness, Genetic Diagnoses That Can Improve Treatments, Using Snps To Identify Disease Genes