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Submitted on February 12, 2004
Accepted on January 14, 2005
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
* To whom correspondence should be addressed. E-mail: kamataki{at}pharm.hokudai.ac.jp.
The expression of CYP2C12 by growth hormone (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 a factor(s) which regulates the gender-related expression of CYP2C12, male rats were treated with trichostatin A, a specific inhibitor of histone deacetylase (HDAC) capable of condensing the chromatin structure. Interestingly, the expression of CYP2C12 by GH was seen even in the livers of male rats, indicating that HDAC contributes to the suppression of CYP2C12 expression in male rats. DNase 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 (GHRE) that bound to STAT5, termed as HS1, was specific for female rat livers, while a hypersensitive site at a position -3 kb, designated as HSm, 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 SV40 promoter. Gel shift assay demonstrated that both C/EBP
and C/EBP
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 STAT5 to the GHRE 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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