PT  - JOURNAL ARTICLE
AU  - Lamba, Vishal
AU  - Lamba, Jatinder
AU  - Yasuda, Kazuto
AU  - Strom, Stephen
AU  - Davila, Julio
AU  - Hancock, Michael L.
AU  - Fackenthal, James D.
AU  - Rogan, Peter K.
AU  - Ring, Barbara
AU  - Wrighton, Steven A.
AU  - Schuetz, Erin G.
TI  - Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to <em>CYP2B6</em> Genotype and CAR (Constitutive Androstane Receptor) Expression
AID  - 10.1124/jpet.103.054866
DP  - 2003 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 906--922
VI  - 307
IP  - 3
4099  - http://jpet.aspetjournals.org/content/307/3/906.short
4100  - http://jpet.aspetjournals.org/content/307/3/906.full
SO  - J Pharmacol Exp Ther2003 Dec 01; 307
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics