Huang Wendong, Zhang Jun, Washington Michele, Liu Jun, Parant John M, Lozano Guillermina, Moore David D
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Endocrinol. 2005 Jun;19(6):1646-53. doi: 10.1210/me.2004-0520. Epub 2005 Apr 14.
The constitutive androstane receptor (CAR, NR1I3) is a central regulator of xenobiotic metabolism. CAR activation induces hepatic expression of detoxification enzymes and transporters and increases liver size. Here we show that CAR-mediated hepatomegaly is a transient, adaptive response to acute xenobiotic stress. In contrast, chronic CAR activation results in hepatocarcinogenesis. In both acute and chronic xenobiotic responses, hepatocyte DNA replication is increased and apoptosis is decreased. These effects are absent in CAR null mice, which are completely resistant to tumorigenic effects of chronic xenobiotic stress. In the acute response, direct up-regulation of Mdm2 expression by CAR contributes to both increased DNA replication and inhibition of p53-mediated apoptosis. These results demonstrate an essential role for CAR in regulating both liver homeostasis and tumorigenesis in response to xenobiotic stresses, and they also identify a specific molecular mechanism linking chronic environmental stress and tumor formation.
组成型雄烷受体（CAR，NR1I3）是异生物质代谢的核心调节因子。CAR激活可诱导解毒酶和转运蛋白在肝脏中的表达，并增加肝脏大小。在此我们表明，CAR介导的肝肿大是对急性异生物质应激的一种短暂的适应性反应。相比之下，慢性CAR激活会导致肝癌发生。在急性和慢性异生物质反应中，肝细胞DNA复制增加而细胞凋亡减少。这些效应在CAR基因敲除小鼠中不存在，这些小鼠对慢性异生物质应激的致瘤作用完全具有抗性。在急性反应中，CAR对Mdm2表达的直接上调作用既促进了DNA复制增加，又抑制了p53介导的细胞凋亡。这些结果证明了CAR在响应异生物质应激时对肝脏稳态和肿瘤发生的调节中起着至关重要的作用，并且它们还确定了一种将慢性环境应激与肿瘤形成联系起来的特定分子机制。
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