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Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.
Kawamoto, T; Kakizaki, S; Yoshinari, K; Negishi, M.
Affiliation
  • Kawamoto T; 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.
Mol Endocrinol ; 14(11): 1897-905, 2000 Nov.
Article in En | MEDLINE | ID: mdl-11075820
ABSTRACT
The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions.
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Database: MEDLINE Main subject: Steroid Hydroxylases / Transcription Factors / Aryl Hydrocarbon Hydroxylases / Receptors, Cytoplasmic and Nuclear / Cytochrome P-450 Enzyme System / Estrogens / Liver Limits: Animals / Female / Humans / Male Language: En Year: 2000 Type: Article
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Database: MEDLINE Main subject: Steroid Hydroxylases / Transcription Factors / Aryl Hydrocarbon Hydroxylases / Receptors, Cytoplasmic and Nuclear / Cytochrome P-450 Enzyme System / Estrogens / Liver Limits: Animals / Female / Humans / Male Language: En Year: 2000 Type: Article