Abstract
The nuclear receptor constitutive active receptor (CAR) translocates into liver nuclei after phenobarbital (PB) treatment, and activates the conserved enhancer called the PB-response element module (PBREM) found in CYP2B genes. We have examined whether CAR regulates the dimorphic induction by PB of the CYP2B1 gene in Wistar Kyoto (WKY) rats. Northern blot analysis showed that PB induced CYP2B1 mRNA in male WKY rats but not female rats. An in situ injected PBREM-luciferase reporter gene was activated by PB only in the male livers. Western blot analysis revealed extremely low levels of CAR in the cytosols of female livers compared with male counterparts. CAR was accumulated in the liver nucleus of male rats in response to PB treatment, whereas the receptor was barely detectable in the liver nuclei of PB-induced females. These sexually dimorphic responses of PBREM and CAR to PB treatment were not observed with Fisher 344 rats, in which CYP2B1 mRNA was induced in both sexes. Thus, these results indicate that CAR is a regulatory factor that leads to the sexual dimorphic induction of CYP2B1 gene in WKY rats.
Footnotes
- Received July 6, 2000.
- Accepted November 2, 2000.
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Send reprint requests to: Dr. Masahiko Negishi, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709. E-mail:negishi{at}niehs.nih.gov
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K.Y. is a Japan Society for the Promotion of Science research fellow and was supported by a grant from The Uehara Memorial Foundation (Tokyo, Japan).
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The nucleotide sequences in this paper have been submitted to the GenBank database with accession numbers AF133094 and AF133095.
- The American Society for Pharmacology and Experimental Therapeutics
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