1998 WHRG Grant Program

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Gender and Ethnic Differences in Drug Metabolism
Maura Whiteman
School of Medicine, University of Maryland, Baltimore

Most drugs are metabolized by the cytochrome P450 (CYP450) system, which is composed of many families of enzymes that differ in structure and specificity of the reactions they catalyze. Genetic polymorphisms have been described in genes that code for several CYP450 enzymes. Such genetic alterations may result in differences in enzyme activity that affect detoxification and/or bioactivation rates of drugs. Additionally, these polymorphisms may be associated with gender and ethnic differences in drug metabolism.

Historically, women were under-represented in clinical drug studies, under the assumption that women and men metabolize and respond to drugs in a similar manner. However, several studies have indicated that there are significant gender differences in the clearance of many clinically important drugs. In addition, women are more likely than men to experience drug side effects. While not influencing the inheritance of CYP450 polymorphisms, factors related to gender may affect the activity of enzymes resulting from polymorphic genes. Certain occurrences specific to females such as menstruation, menopause, pregnancy, and oral contraceptive use may profoundly affect CYP450-mediated metabolism.

Differences in drug metabolism among racial/ethnic groups have also been described. Asian- Americans have an increased sensitivity to beta-blockers, while African Americans are less responsive to ACE inhibitors than Caucasians. The distributions of polymorphisms in genes coding for CYP450 enzymes among racial/ethnic groups may contribute to these observed differences in drug metabolism.

We propose a pilot study to assess the feasibility of conducting a large-scale, cross-sectional study to test three hypotheses regarding gender and ethnic differences in drug metabolism:

The distribution of genetic polymorphisms in the genes coding for enzymes of the CYP450 system differ among racial/ethnic groups,
Polymorphisms in genes coding for CYP450 enzymes are associated with gender differences in drug metabolism, and
Polymorphisms in genes coding for CYP450 enzymes are associated with racial/ethnic differences in drug metabolism.

As part of the pilot study, 200 men and women of varying ethnic backgrounds will complete a brief questionnaire to ascertain their use of medications, medical history, and reproductive history (in females). Participants will also donate a small amount of blood form which DNA will be isolated and evaluated for the presence of polymorphisms using PCR in the genes coding for two CYP450 enzymes. Differences in the distribution of polymorphisms among racial/ethnic groups will be evaluated. Multiple regression analysis will assess the association between these polymorphisms and drug side effects among gender and/or ethnic groups.

If successful, methods from this pilot study will be adapted for a large-scale study in which the distribution of genetic polymorphisms and their effect on drug metabolism may be further evaluated. Ultimately, the results of this study may lead to screening tests to identify gender and/or ethnic groups as well as individuals that are at increased risk for drug toxicity, increased side effects, or even therapeutic failure.