CYP3A4 Gene Polymorphisms Influence Testosterone 6β-hydroxylation

doi:10.2133/dmpk.17.150

Drug Metabolism and Pharmacokinetics

Volume 17, Issue 2, 2002, Pages 150-156

https://doi.org/10.2133/dmpk.17.150 Get rights and content

Summary:

Three non-synonymous single nucleotide polymorphisms (SNPs) in the CYP3A4 gene were found in 34 cell lines derived from Japanese individuals. These three SNPs (T185S, L293P, and T363M)¹ have been previously reported, but little is known about the effect that these polymorphisms, especially T185S, have on catalytic activity. We measured testosterone hydroxylation in wild-type CYP3A4 and these three variants using a mammalian expression system. Testosterone 6β-, 2β-, and 15β-hydroxylations by the variant CYP3A4 forms T363M (< 40%) and T185S (< 60%) were reduced as compared with the wild-type in transient expression assays. L293P was similar to the wild-type in testosterone 6β- and 2β-hydroxylase activities. Western blot analysis confirmed lower amounts of CYP3A4 protein in the T363M and T185S variants than in the wild-type. Interestingly, Northern blot analysis showed no significant difference among mRNA levels between the wild-type and variants. These results suggest that the T363M and T185S substitutions in CYP3A4 affect either protein expression or stability. These established cell lines provided useful CYP3A4 SNP information in the Japanese.

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Cytochrome P450 (CYP) 3A4 is a clinically significant oxidative enzyme that is involved in the metabolism of >50% of drugs used in the clinical setting, as well as certain endogenous substances (e.g., steroids) [1].
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Regular ArticleCYP3A4 Gene Polymorphisms Influence Testosterone 6β-hydroxylation

Summary:

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Arch. Biochem. Biohys.

J. Mol. Biol.

J. Biol. Chem.

Mol. Cell.

J. Biol. Chem.

J. Biol. Chem.

Structure, Mechanism and Biochemistry

Evidence for cytochrome P-450NF, the nifedipine oxidase, being the principal enzyme involved in the bioactivation of aflatoxins in human liver

Proc. Natl. Acad. Sci. U S A

Non-invasive tests of CYP3A enzymes

Pharmacogenetics

Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions

Clin. Pharmacokinet.

Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics

Science

Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online

Hum Mutat.

CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity

Clinical Pharmacol. Ther.

Molecular genetics of the Finnish disease heritage

Hum. Mol. Genet.

Regular Article
CYP3A4 Gene Polymorphisms Influence Testosterone 6β-hydroxylation