Estrogen activation of the nuclear orphan receptor CAR (Constitutive active receptor) in induction of the mouse Cyp2b10 gene
Estrogen activation of the nuclear orphan receptor CAR (Constitutive active receptor) in induction of the mouse Cyp2b10 gene
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DOI：
10.1210/me.14.11.1897
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发表时间：
2000-11-01
影响因子：
--
通讯作者：
Negishi, M
中科院分区：
文献类型：
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作者：
Kawamoto, T;Kakizaki, S;Negishi, M
核孤儿受体 CAR（组成型活性受体或组成型雄甾烷受体）可以响应异种化学暴露而被激活，例如苯巴比妥激活 CYP2B 基因中名为 NR1 的反应元件。这里，使用转染的 HepG2 细胞和/或小鼠原代肝细胞中的 NR1 增强子和 Cyp2b10 诱导作为实验标准，筛选各种类固醇中可能激活 CAR 的潜在内源化学物质。 17β-雌二醇和雌酮可激活 NR1，而雌三醇、雌四醇、硫酸雌二醇和合成雌激素己烯雌酚则不会。另一方面，黄体酮和雄激素抑制HepG2细胞中的NR1活性，而被抑制的NR1活性被雌二醇完全恢复。此外，雌激素治疗引起小鼠肝脏和原代肝细胞中CAR的核积累，并诱导内源性Cyp2b10基因。卵巢切除不影响雌性肝核中CAR的基础水平或诱导水平，而去势则略微增加了雄性小鼠肝核中的基础水平并大大增加了诱导水平。因此，内源性雌激素似乎不会调节雌性小鼠的 CAR，而内源性雄激素可能是雄性小鼠的抑制因素。在雌性和雄性小鼠中，药理学水平的雌激素是 CAR 的有效激活剂，表明该受体在雌激素代谢中具有生物学和/或毒理学作用。除了小鼠 CAR 之外，雌激素还能激活大鼠 CAR，而人类 CAR 在实验条件下对雌激素反应不佳。
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. 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 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.