Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor
Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor
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DOI：
10.1210/me.2004-0520
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发表时间：
2005-06-01
影响因子：
--
通讯作者：
Moore, DD
中科院分区：
文献类型：
--
作者：
Huang, WD;Zhang, J;Moore, DD
组成型雄烷受体（CAR，NR1I3）是异生物质代谢的中心调节剂。CAR活化诱导解毒酶和转运蛋白的肝脏表达并增加肝脏大小。在这里，我们表明CAR介导的肝肿大是对急性外源性应激的短暂适应性反应。相反，慢性CAR激活导致肝癌发生。在急性和慢性外源性反应中，肝细胞DNA复制增加，细胞凋亡减少。这些作用在CAR缺失小鼠中不存在，其对慢性外源性应激的致瘤作用完全耐受。在急性反应中，CAR直接上调Mdm2表达有助于增加DNA复制和抑制p53介导的细胞凋亡。这些结果表明CAR在调节肝脏稳态和肿瘤发生中响应于异生物质应激的重要作用，并且它们还确定了连接慢性环境应激和肿瘤形成的特定分子机制。
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.