Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 307, Issue 3, Pages 906-922Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.103.054866
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Funding
- NATIONAL CANCER INSTITUTE [R29CA051001, P30CA021765, R01CA051001] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [N01DK092310] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES010855] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM060346, U01GM061374] Funding Source: NIH RePORTER
- NCI NIH HHS [CA 51001, P30 CA 21765] Funding Source: Medline
- NIDDK NIH HHS [N01-DK-9-2310] Funding Source: Medline
- NIEHS NIH HHS [ES 10855] Funding Source: Medline
- NIGMS NIH HHS [U01 GM 61374, GM 60346] Funding Source: Medline
- PHS HHS [U01 61393] Funding Source: Medline
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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.
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