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The genetics behind drug breakdown. (Pharmaceuticals).

Individuals with a common genetic variation may not metabolize certain drugs as readily as those without the mutation, researchers report in the April 2001 Nature Genetics. As a result, they may be particularly sensitive to these medications. This finding is a "big step forward" toward understanding the genetic variants behind drug reactions, says Rochelle M. Long, head of the NIH Pharmacogenetics Research Network, which helped fund the study.

The protein CYP3A5 is part of the family of CYP3A enzymes, which break down cholesterol-lowering, anticancer, anti-HIV, and immunosuppressant drugs passing through the digestive system. Research from the late 1980s had shown that CYP3A5 helps metabolize drugs, yet is not in the tissues of some people. The new study reveals that these individuals have one of two variant alleles that express only short, inactive versions of CYP3A5, report scientists led by Erin Schuetz, a pharmaceutical scientist at St. Jude Children's Research Hospital in Memphis, Tennessee. One normal allele is needed for the body to express the active protein.

In the United States, 60% of African Americans and only 25-30% of Caucasians have the active protein, the team reports. People without the protein may need smaller doses of the drugs it normally metabolizes, or they risk side effects, Schuetz explains. "CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in response to many medicines," the team concludes. CYP3A proteins break down 50% of clinical drugs, and CYP3A5 is the most common of the proteins, normally representing as much as half of all CYP3A enzymes, Schuetz says.

In their study, Schuetz and colleagues analyzed DNA samples from 159 individuals. They first identified the most common single nucleotide polymorphisms in the CYP3A genes. Then they related these variants to differences in how the participants metabolized midazolam, a common sedative. People who metabolized the drug slowly were found to carry the CYP3A5*3 or CYP3A5*6 alleles, and the faster metabolizers carried CYP3A5*1.

Depending on the variant, CYP3A5 proteins can affect how the body metabolizes certain environmental contaminants, including aflatoxins, compounds produced by molds and found in some animal feeds and peanuts, Schuetz says. They can either help the body break down the contaminant, or they can take the contaminant from an inert to a DNA-damaging form. So the CYP3A5 allele that people carry may also influence their susceptibility to environmental diseases, she says.

Companies are interested in marketing CYP3A tests, and pharmacogenetic tests to show whether a person has genetic variants that could affect his or her response to drugs may become widely available within the next few years, says Long. Researchers can already identify the CYP3A5 protein by analyzing buccal cells, explains Schuetz. Nevertheless, before tests for genetic variations become routine, "there will be lots of clinical studies to determine for many [medications] the importance of whether you have 3A5 or not," she explains. "Second, for those drugs where 3A5 is making a difference, there may be testing to guide appropriate dosing."
COPYRIGHT 2001 National Institute of Environmental Health Sciences
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Author:Adler, Tina
Publication:Environmental Health Perspectives
Date:Sep 1, 2001
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