Rx For Drug Toxicity: Medicine Made To Match Genetic Profile

Don't blame the drug, says Wendell Weber, M.D., Ph.D., a medical geneticist at the University of Michigan Medical School. The real problem is likely to be your genes.

"Physicians and patients understand that genes influence health and disease, but most don't realize the harmful effects pharmaceutical drugs can have on genetically susceptible people," explains Weber, a U-M professor emeritus of pharmacology. "Genetic diversity is a major contributor to variations in human drug response."

A pioneer in the field of pharmacogenetics, Weber devoted his career to studying how small genetic mutations called polymorphisms can lead to big differences in how people respond to drugs or environmental chemicals. The same drug that helps one individual may have no affect, or even harm, someone else.

As the Human Genome Project nears completion, pharmacogenetics is getting a lot of attention, because it could make it possible for physicians to prescribe safer and more effective drugs and therapies tailored to each patient's unique genetic code.

During the "2001 Genome Seminar: Beyond the Human Genome," at the annual meeting of the American Association for the Advancement of Science held here Feb. 15-20, Weber explained how the science of pharmacogenetics developed over the past 40 years. He also discussed the emergence of a related field called pharmacogenomics, which analyzes all the polymorphisms in the entire genome.

"There are millions of polymorphisms in the human genome," Weber says. "Fortunately, only a limited number affect how people react to drugs or environmental substances. We already have identified many of them, and data from the Human Genome Project should make it easy to find the others."

The polymorphisms Weber studies can be as small as a one-for-one substitution of amino acids in a gene made up of thousands of amino acids. Like other genetic mutations, they are inherited and can involve single or multiple genes.

One group of polymorphic mutations produces defects in drug-metabolizing enzymes, while another group is associated with unusually sensitive or resistant responses to drugs. Polymorphisms in genes for receptor molecules can prevent drugs from passing through cell membranes, or can interrupt the chain of biochemical signals cells use to communicate.

"Population frequencies of many polymorphic genes vary with race or ethnic background," Weber says. "For example, a condition called primaquine sensitivity is responsible for the reaction of many African, Mediterranean and Asian men to certain drugs. Another mutated gene accounts for the remarkable sensitivity of the Japanese to alcohol."

Other genetic polymorphisms are associated with extreme sensitivity to specific foods, type one diabetes, a serious heart condition called long QT syndrome, susceptibility to asthma, a bleeding disorder called thrombophilia, and an inability to metabolize common drugs like codeine, beta-blockers and antidepressants, which can result in dangerous overdoses.

The next big challenge will be determining the effects of each polymorphism on individual proteins, enzymes and receptors in cells, according to Weber. "A great deal of basic research will be needed," Weber says. "We can't just crank up machines and get the answers."

Advances in bioinformatics and DNA microarray technology, which make it possible to monitor the activity of all genes simultaneously, will be needed before pharmacogenomics can live up to its full potential in medicine, adds Weber. And physicians and pharmacists will need advanced training to extend the benefits of individualized medicine to their patients.

Weber has written two books on pharmacogenetics: "Acetylator Genes and Drug Response" (1987) and "Pharmacogenetics" (1997), both published by Oxford University Press.