On their journey through the body, medicines interact with many different proteins. Some of these proteins work to get rid of medicines, while others help medicines do their jobs treating or preventing illness. Small differences between people in the genes that produce these proteins can affect how people react--or don't react--to certain medicines. Very slight changes in a gene can cause its protein product to be defective, or such changes can lead to either over-or underproduction of the protein. Partly because of these gene differences, when it comes to medicines, one size clearly does not fit all.
Dr. Erin Schuetz of St. Jude Children's Research Hospital has uncovered the genetic basis for why some people do not produce sufficient levels of a drug-metabolizing protein called CYP3A5, which is believed to be capable of metabolizing nearly half of all medicines.1 Dr. Schuetz and her coworkers found several "single-letter" changes in the DNA spellings of the gene that produces the CYP3A5 protein that affect how much of the protein is manufactured. Moreover, the researchers discovered that racial and ethnic background play a role in determining CYP3A5 protein levels, offering a genetic explanation for why certain individuals from particular racial and ethnic groups can display such a varied response to medicines like HIV protease inhibitors, cholesterol-lowering drugs, organ rejection treatments, and cancer chemotherapy medicines. The study showed that only 25 percent of Americans of European descent and 50 percent of Asians and African Americans produce enough of the CYP3A5 protein to break down drugs properly and avoid reactions caused by the buildup of toxic breakdown products.
The new work provides an explanation for why some people react so differently to a broad range of medicines. The research may lead to genetic tests that could help doctors prescribe accurate doses of medicines based upon patients' ability to metabolize certain drugs. Correct dosing of many CYP3A5-processed medicines with potentially fatal toxicities, such as some forms of cancer chemotherapy and organ rejection treatments, will make these therapies safer and more effective.
REFERENCE
1Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, and Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet. 2001;27:383-91.
Reporters may call the NIGMS Office of Communications and Public Liaison at (301) 496-7301 to obtain the name of an NIGMS scientist who can comment on this work.
