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/mend.14.11.0547
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发表时间：
2000-11
影响因子：
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通讯作者：
T. Kawamoto;Satoru Kakizaki;Kouich Yoshinari;M. Negishi
中科院分区：
文献类型：
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作者：
T. Kawamoto;Satoru Kakizaki;Kouich Yoshinari;M. Negishi
核孤儿受体CAR（组成型活性受体或组成型雄烷受体）可响应于异种化学品暴露而被激活，例如通过苯巴比妥激活CYP 2B基因中发现的称为NR 1的响应元件。在此，使用转染的HepG 2细胞和/或小鼠原代肝细胞中的NR 1增强子和Cyp 2b 10诱导作为实验标准，筛选各种类固醇中可能激活CAR的潜在内源性化学物质。17 β-雌二醇和雌酮激活NR 1，而雌三醇、雌四醇、硫酸雌二醇和合成雌激素己烯雌酚则没有。另一方面，孕激素和雄激素抑制NR 1活性在HepG 2细胞，和抑制NR 1活性完全恢复雌二醇。此外，雌激素处理引起CAR在小鼠肝脏以及原代肝细胞中的核积累，并诱导内源性Cyp 2b 10基因。卵巢切除术不影响雌性小鼠肝细胞核中CAR的基础或诱导水平，而去势略微增加了雄性小鼠肝细胞核中CAR的基础和诱导水平。因此，内源性雌激素似乎不调节雌性小鼠中的CAR，而内源性雄激素可能是雄性小鼠中的抑制因子。药理学水平的雌激素是雌性和雄性小鼠中CAR的有效激活剂，表明该受体在雌激素代谢中的生物学和/或毒理学作用。除了小鼠CAR，雌激素激活大鼠CAR，而人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. 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.