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Novel Gender-Related Regulation of CYP2C12 Gene Expression in Rats

Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan

Address all correspondence and requests for reprints to: Dr. Tetsuya Kamataki, Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan. E-mail: kamataki{at}pharm.hokudai.ac.jp

The expression of CYP2C12 by GH occurs in female but not in male rat livers. Direct injection of the CYP2C12 promoter-luciferase gene into male rat livers showed that the CYP2C12 promoter was active in both male and female rats. Thus, to further examine one or more factors that regulate the gender-related expression of CYP2C12, male rats were treated with trichostatin A, a specific inhibitor of histone deacetylase capable of condensing the chromatin structure. Interestingly, the expression of CYP2C12 by GH was seen even in the livers of male rats, indicating that histone deacetylase contributes to the suppression of CYP2C12 expression in male rats. Deoxyribonuclease I hypersensitive assay using nuclei from the livers of male or female rats revealed that the chromatin structure of the CYP2C12 gene was gender specific: a hypersensitive site at a position –4.2 kb containing GH-responsive element that bound to signal transducer and activator of transcription 5 (STAT5), termed as HS (hypersensitive site) 1, was specific for female rat livers, whereas a hypersensitive site at a position –3 kb, designated as HSm (male-specific hypersensitive site), was characteristic of male rat livers. A –3425/–3275 region within HSm functioned as a negative regulatory region, when the region was inserted in front of simian virus 40 promoter. Gel shift assay demonstrated that both CCAAT/enhancer-binding protein and ß bound to the –3425/–3275 region. Based on these results, we conclude that the gender-related expression of the CYP2C12 gene results from the inaccessibility of to STAT5 to the GH-responsive element by chromatin condensation seen in male rat livers, and from the presence of the male-specific HSm that acts as a silencer.

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