Journal Article

Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression

Lin, Yvonne, Brimer, Cynthia, Boguski, Mark S., Kuehl, Peter, Maurel, Patrick, Relling, Mary, Zhang, Jiong, Schuetz, John, Hall, Stephen D., Wrighton, Steven A., Venkataramanan, Raman, Thummel, Kenneth, Daly, Ann, Schuetz, Erin, Lamba, Jatinder, Strom, Stephen, Watkins, Paul B., Assem, Mahfoud, Yasuda, Kazuto

2001

Overview

Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5 , which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5 * 1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5 * 3 and CYP3A5 * 6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Alleles / Alternative Splicing / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Continental Population Groups / CYP3A5 gene / Cytochrome / Cytochrome P-450 CYP3A / Cytochrome P-450 Enzyme System - genetics / Drug metabolism / Enzymes / Estrogens / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Function / Genes / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Human / Human Genetics / Humans / Metabolism / Minority & ethnic groups / Molecular Sequence Data / Polymorphism, Single Nucleotide / Population genetics, reproduction patterns / Promoter Regions, Genetic / Promoters (Genetics) / Publishing / Steroids / White people