Nuclear receptor CAR as a regulatory factor for the sexually dimorphic induction of CYB2B1 gene by phenobarbital in rat livers.
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.
Yoshinari
K
K
Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Sueyoshi
T
T
Moore
R
R
Negishi
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012727:Sex Characteristics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors
D000090702:Constitutive Androstane Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D019362:Cytochrome P-450 CYP2B1; D010634:Phenobarbital