Estrogen activation of the nuclear orphan receptor CAR (Constitutive active receptor) in induction of the mouse Cyp2b10 gene

The nuclear orphan receptor CAR (constitutively active receptor or constitu tive androstane receptor) can be activated in response to xenochemical expo sure, 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 Cyp2 b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17 beta -Estradiol and estrone activated NR1 , whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens r epressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fu lly restored by estradiol. Moreover, estrogen treatment elicited nuclear ac cumulation 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 ca stration slightly increased the basal and greatly increased the induced lev els in the liver nucleus of male mice. Thus, endogenous estrogen appears no t to regulate CAR in female mice, whereas endogenous androgen may be the re pressive factor in male mice. Estrogen at pharmacological levels is an effe ctive activator of CAR in both female and male mice, suggesting a biologica l and/or toxicological role of this receptor in estrogen metabolism. In add ition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions.