Cause of Human Drug Metabolism Variations Identified

Erin Schuetz
St. Jude Childrens Research Hospital
R01ES08658

Background: The Environmental Genome Project at NIEHS seeks to identify gene variations in the human genome that make some people more resistant or susceptible to diseases induced by environmental agents. This gene/environment interaction is a major research focus for NIEHS. Scientists have known that people express differing levels of a family of enzymes known as cytochrome P450s based on their genetic makeup. The enzymes are responsible for metabolism of innate and foreign compounds. Approximately 55 different genes have been identified that code for the various cytochrome P450s.

Advance: This paper describes the identification of variations in the gene for cytochrome P450-3A5 (CYP3A5). Members of the CYP3A family make up almost half of the total cytochromes found in liver tissue and are responsible for the metabolism of estrogens and many drugs including HIV protease inhibitors, calcium channel blockers, cholesterol reducing agents, cancer chemotherapeutics, and transplant rejection drugs. The results indicate that the substitution of a single incorrect nucleotide, also known as a single nucleotide polymorphism, in the structure of the CYP3A5 gene disrupts the activity of the enzyme. Further genetic analyses demonstrated that only 30% of Caucasians and over 50% of African Americans and Asians have the normal gene and produce normal levels of CYP3A5. These differences in expression are much larger than previously believed.

Implication: Based on these findings, the team predicts many patients will eventually be screened for CYP3A5 activity. Those with low activity will likely have doses of chemotherapeutic and immune suppression drugs reduced to reduce associated toxicities and improve therapeutic responses. The ability to express CYP3A5 may prove to be the most important element in population differences in drug metabolism.

Citation: Kuehl 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, Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001 Apr;27(4):383-91.