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

Abstract

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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Figure 1: Splice variants of CYP3A5.
Figure 2: Relationship between CYP3A5 phenotype and CYP3A5 genotype in livers of Caucasians (a) and African Americans (b).
Figure 3: Rates of midazolam hydroxylation in livers with different CYP3A5 genotypes.
Figure 4: Association between CYP3A5 expression and CYP3A5 genotype in human liver and small intestine.

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Acknowledgements

We thank E. Green for advice and use of facilities. This work was supported in part by grant GM60346 and the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org/) under grant U01GM (GM61393) and by grants GM32165, ES08658, P30 CA21765, and CA51001 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities (ALSAC).

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Correspondence to Erin Schuetz.

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Kuehl, P., Zhang, J., Lin, Y. et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27, 383–391 (2001). https://doi.org/10.1038/86882

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