title: In vitro analysis of factors influencingCYP1A2expression as potential determinants of interindividual variation.
abstract: Individual differences in drug metabolism contribute to interindividual variation that characterizes responses to drugs and risk in exposure to foreign chemicals. Large individual differences are found in expression levels ofCYP1A2, a major drug-metabolizing enzyme. Underlying causes for this variation are not well understood. Several factors, including tobacco smoking, consumption of cruciferous vegetables, and sex, have been associated with modulatingCYP1A2expression. To understand factors regulating expression ofCYP1A2in establishing a causal relationship, this study examined effects of cigarette smoke condensate (CSC), indole-3-carbinol (I3C), and 17β-estradiol (estradiol) on CYP1A2 expression in in vitro systems using human liver and lung cells. Treatment with CSC (2-25μg/mL) significantly increased levels ofCYP1A2in six cell lines examined, in a concentration- and time-dependent manner. Fold changes in expression levels relative to controls varied among cell lines. CYP1A2 enzymatic activity also increased with CSC exposure. Treatment of H1299 and HepB3 cells with dietary agent I3C (50 and 100μmol/L) increasedCYP1A2expression. In human cell lines H1299 and H1395, treatment with estradiol (10 and 100 nmol/L) significantly reduced expression ofCYP1A2. Using ChIP assays, effects of CSC on histone modifications were analyzed. Increases in H3K4me3 and H4K16ac were observed at several segments in theCYP1A2gene, whereas H3K27me3 decreased, following CSC treatment. These results suggest thatCYP1A2expression is affected epigenetically by CSC. Additional studies will be needed to further establish regulatory mechanisms underlying effects of various environmental, dietary, and endogenous factors onCYP1A2expression in better predicting individual variation.
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: ChengHui
authors.initials: C
authors.lastname: Xie
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: Marta
authors.initials: M
authors.lastname: Pogribna
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: Beverly
authors.initials: B
authors.lastname: Word
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: Lascelles
authors.initials: L
authors.lastname: Lyn-Cook
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: Beverly D
authors.initials: BD
authors.lastname: Lyn-Cook
authors.affiliation: Division of Biochemical Toxicology FDA/National Center for Toxicological Research Jefferson Arkansas 72079.
authors.forename: George J
authors.initials: GJ
authors.lastname: Hammons
keywords: CYP1A2; Cigarette smoke condensate; histone modifications; human cells