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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to CYP2B6 Genotype and CAR (Constitutive Androstane Receptor) Expression

Vishal Lamba, Jatinder Lamba, Kazuto Yasuda, Stephen Strom, Julio Davila, Michael L. Hancock, James D. Fackenthal, Peter K. Rogan, Barbara Ring, Steven A. Wrighton and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics December 2003, 307 (3) 906-922; DOI: https://doi.org/10.1124/jpet.103.054866
Vishal Lamba
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Jatinder Lamba
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Kazuto Yasuda
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Stephen Strom
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Julio Davila
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Michael L. Hancock
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James D. Fackenthal
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Peter K. Rogan
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Barbara Ring
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Steven A. Wrighton
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Erin G. Schuetz
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Abstract

CYP2B6 metabolizes many drugs, and its expression varies greatly. CYP2B6 genotype-phenotype associations were determined using human livers that were biochemically phenotyped for CYP2B6 (mRNA, protein, and CYP2B6 activity), and genotyped for CYP2B6 coding and 5′-flanking regions. CYP2B6 expression differed significantly between sexes. Females had higher amounts of CYP2B6 mRNA (3.9-fold, P < 0.001), protein (1.7-fold, P < 0.009), and activity (1.6-fold, P < 0.05) than did male subjects. Furthermore, 7.1% of females and 20% of males were poor CYP2B6 metabolizers. Striking differences among different ethnic groups were observed: CYP2B6 activity was 3.6- and 5.0-fold higher in Hispanic females than in Caucasian (P < 0.022) or African-American females (P < 0.038). Ten single nucleotide polymorphisms (SNPs) in the CYP2B6 promoter and seven in the coding region were found, including a newly identified 13072A>G substitution that resulted in an Lys139Glu change. Many CYP2B6 splice variants (SV) were observed, and the most common variant lacked exons 4 to 6. A nonsynonymous SNP in exon 4 (15631G>T), which disrupted an exonic splicing enhancer, and a SNP 15582C>T in an intron-3 branch site were correlated with this SV. The extent to which CYP2B6 variation was a predictor of CYP2B6 activity varied according to sex and ethnicity. The 1459C>T SNP, which resulted in the Arg487Cys substitution, was associated with the lowest level of CYP2B6 activity in livers of females. The intron-3 15582C>T SNP (in significant linkage disequilibrium with a SNP in a putative hepatic nuclear factor 4 (HNF4) binding site) was correlated with lower CYP2B6 expression in females. In conclusion, we found several common SNPs that are associated with polymorphic CYP2B6 expression.

Footnotes

  • ABBREVIATIONS: SNP, single nucleotide polymorphism; CAR, constitutive androstane receptor; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; SV, splice variant; ESE, exonic splicing enhancer; SR, serine/arginine-rich; PBREM, phenobarbital-responsive enhancer module; XREM, xenobiotic-responsive enhancer module; HNF, hepatic nuclear factor; Sp-1, simian virus 40 promoter factor 1; LD, linkage disequilibrium; SIFT, sorting intolerant from tolerant; PGC-1α, peroxisome proliferator-activated receptor 1α.

  • Normal human liver and hepatocytes were obtained through the Liver Tissue Procurement and Distribution System (Pittsburgh, PA), which was funded by National Institutes of Health (NIH) Contract N01-DK-9-2310.

  • This work is supported in part by NIH Grant GM60346; by the NIH/National Institute of General Medical Sciences (NIGMS) Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org) under grant U01 GM61393; by NIH Grant P30 CA21765; by NIH Grant ES 10855; by NIH Grant CA51001; and by the American Lebanese Syrian Associated Charities (ALSAC).

  • DOI: 10.1124/jpet.103.054866.

    • Received May 21, 2003.
    • Accepted August 22, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 3
1 Dec 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to CYP2B6 Genotype and CAR (Constitutive Androstane Receptor) Expression

Vishal Lamba, Jatinder Lamba, Kazuto Yasuda, Stephen Strom, Julio Davila, Michael L. Hancock, James D. Fackenthal, Peter K. Rogan, Barbara Ring, Steven A. Wrighton and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 906-922; DOI: https://doi.org/10.1124/jpet.103.054866

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to CYP2B6 Genotype and CAR (Constitutive Androstane Receptor) Expression

Vishal Lamba, Jatinder Lamba, Kazuto Yasuda, Stephen Strom, Julio Davila, Michael L. Hancock, James D. Fackenthal, Peter K. Rogan, Barbara Ring, Steven A. Wrighton and Erin G. Schuetz
Journal of Pharmacology and Experimental Therapeutics December 1, 2003, 307 (3) 906-922; DOI: https://doi.org/10.1124/jpet.103.054866
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