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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of Variants of CYP3A4 and Characterization of Their Abilities to Metabolize Testosterone and Chlorpyrifos

Diana Dai, Jun Tang, Randy Rose, Ernest Hodgson, Rachelle J. Bienstock, Harvey W. Mohrenweiser and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 825-831;
Diana Dai
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Jun Tang
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Randy Rose
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Ernest Hodgson
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Rachelle J. Bienstock
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Harvey W. Mohrenweiser
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Joyce A. Goldstein
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Abstract

CYP3A4 is the most abundant isoform of cytochrome P450 (CYP) in adult human liver. It metabolizes numerous clinically, physiologically, and toxicologically important compounds. The expression of CYP3A4 varies 40-fold in individual human livers, and metabolism of CYP3A4 substrates varies at least 10-fold in vivo. Single nucleotide polymorphisms (SNPs) in CYP3A4 were identified by direct sequencing of genomic DNA in 72 individuals from three different ethnic groups, including Caucasians, Blacks (African-Americans and African pygmies), and Asians. A total of 28 SNPs were identified, including five which produced coding changes M445T (CYP3A4*3), R162Q (CYP3A4*15), F189S (CYP3A4*17), L293P (CYP3A4*18), and P467S (CYP3A4*19). The latter four represent new alleic variants. Racial variability was observed for the frequency of individual SNPs. CYP3A R162Q was identified only in Black populations with an allelic frequency of 4%. CYP3A4 F189S and CYP3A4 M445T were identified in Caucasians with allelic frequencies 2% and 4%, respectively. L293P and P467S were only observed in Asians at allelic frequencies of 2%. The cDNAs for the F189S, L293P, M445T, and P467S mutant alleles were constructed by site-directed mutagenesis and expressed in an Escherichia coli expression system. Testosterone and the insecticide chlorpyrifos were used to assess the catalytic activities of the most common CYP3A4 allele (CYP3A4*1) and its allelic variants. CYP3A4 F189S exhibited lower turnover numbers for testosterone and chlorpyrifos, while CYP3A4 L293P had higher turnover numbers for both substrates. The turnover numbers of the CYP3A4 M445T and P467S alleles to metabolize these compounds were not significantly different from those of wild-type CYP3A4 .

Footnotes

  • ↵1 New CYP3A4 alleles were submitted to the CYP allele web page (www.imm.ki.se/CYPalleles). The names designated by the international allele nomenclature committee areCYP3A4*17 (F189S) and CYP3A4*18 (L292P and CYP23A4*19 (P467S). R162Q was submitted to the CYP3A4 allele web page by another laboratory while this work was in progress and was designated CYP3A4*15 but has not yet been published otherwise.

  • Work at Lawrence Livermore National Laboratory was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory; contract No. W-7405-ENG-48 and supported by interagency agreement Y1-ES-8054-05 from the National Institute of Environmental Health Sciences (H.W.M.). The work at North Carolina State University (J.T., R.R., and E.H.) was supported, in part, by the North Carolina Department of Agriculture Pesticide Environmental Trust Fund and U.S. Army Grant DAMD 17-00-2-0008.

  • Abbreviations:
    CYP
    cytochrome P450
    SNP
    single nucleotide polymorphism
    OPs
    organophosphorus
    TLC
    thin layer chromatography
    TCP
    trichloropyridinol
    CPO
    chlorpyrifos-oxon
    PCR
    polymerase chain reaction
    HPLC
    high-pressure liquid chromatography
    NADPH
    β-nicotinamide adenine dinucleotide phosphate, reduced form
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
    • Received June 22, 2001.
    • Accepted September 12, 2001.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of Variants of CYP3A4 and Characterization of Their Abilities to Metabolize Testosterone and Chlorpyrifos

Diana Dai, Jun Tang, Randy Rose, Ernest Hodgson, Rachelle J. Bienstock, Harvey W. Mohrenweiser and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 825-831;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of Variants of CYP3A4 and Characterization of Their Abilities to Metabolize Testosterone and Chlorpyrifos

Diana Dai, Jun Tang, Randy Rose, Ernest Hodgson, Rachelle J. Bienstock, Harvey W. Mohrenweiser and Joyce A. Goldstein
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 825-831;
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