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Article
Nature Genetics  27, 383 - 391 (2001)
doi:10.1038/86882

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

Peter Kuehl1, 2, 13, Jiong Zhang2, 3, 13, Yvonne Lin4, Jatinder Lamba5, Mahfoud Assem5, John Schuetz5, Paul B. Watkins6, Ann Daly7, Steven A. Wrighton8, Stephen D. Hall9, Patrick Maurel10, Mary Relling5, Cynthia Brimer5, Kazuto Yasuda5, Raman Venkataramanan11, Stephen Strom12, Kenneth Thummel4, Mark S. Boguski2 & Erin Schuetz5

1  Department of Molecular and Cell Biology, University of Maryland at Baltimore, Baltimore, Maryland, USA.

2  National Center for Biotechnology Information, National Institute of Health, Bethesda, Maryland, USA.

3  McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.

4  Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.

5  Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

6  University of North Carolina, Chapel Hill, North Carolina, USA.

7  Department of Pharmacological Sciences, University of Newcastle Upon Tyne, Newcastle, UK.

8  Department of Drug Metabolism, Eli Lilly & Co., Indianapolis, Indiana, USA.

9  Department of Clinical Pharmacology, Indiana University, Indianapolis, Indiana, USA.

10  INSERM, Montpellier, France.

11  Department of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

12  Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

13  These authors contributed equally to this work.

Correspondence should be addressed to Erin Schuetz erin.schuetz@stjude.org
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.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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