Pathophysiological factors affecting CAR gene expression
Pathophysiological factors affecting CAR gene expression
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DOI：
10.1081/dmr-120026394
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发表时间：
2003-01-01
影响因子：
5.9
通讯作者：
Vilarem, MJ
中科院分区：
文献类型：
--
作者：
Pascussi, JM;Dvorák, Z;Vilarem, MJ
人体通过诱导参与代谢和消除的酶和转运体的表达来防御潜在的有害化合物，如药物和有毒的内源性化合物及其代谢物。孤儿核受体CAR(NR113)控制着参与药物代谢和胆红素清除的I期(CYP2B、CYP2C、CYP3A)、11期(UGT1A1)和转运蛋白(SLC21A6、MRP2)基因。组成性雄烷受体(CAR)既可被外源物质如苯巴比妥激活，也可被有毒内源性化合物如胆红素代谢物(S)激活。为了更好地了解药物戒毒的内部和内部变异性，我们研究了涉及人肝细胞CAR基因表达的分子机制。我们明确认为CAR是糖皮质激素受体(GR)的靶基因，并提出了GR激活在CAR介导的细胞反应中起关键作用的信号转导假说。根据我们的模型，影响GR功能的化学物质或病理生理因素应该降低CAR功能。为了验证这一假设，我们最近研究了微管干扰剂(MIA)或促炎细胞因子的作用。这些化合物是众所周知的GR反式激活特性的抑制剂。MIA激活c-jun氨基末端激酶(JNK)，使GR磷酸化并失活，而促炎细胞因子，如IL-6或IL-1β，分别诱导AP-1或NF-kB激活，导致GR抑制。正如我们所预期的那样，我们观察到这些分子同时抑制了人肝细胞中CAR基因的表达和苯巴比妥介导的CYP基因的表达。
The body defends itself against potentially harmful compounds, such as drugs and toxic endogenous compounds and their metabolites, by inducing the expression of enzymes and transporters involved in their metabolism and elimination. The orphan nuclear receptor CAR (NR113 controls phase I (CYP2B, CYP2C, CYP3A), phase 11 (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance. Constitutive androstane receptor (CAR) is activated by xenobiotics, such as phenobarbital, but also by toxic endogenous compounds such as bilirubin metabolite(s). To better understand the inter- and intravariability in drug detoxification, we studied the molecular mechanisms involved in CAR gene expression in human hepatocytes. We clearly identified CAR as a glucocorticoid receptor (GR) target gene, and we proposed the hypothesis of a signal transduction where the activation of GR plays a critical function in CAR-mediated cellular response. According to our model, chemicals or pathophysiological factors that affect GR function should decrease CAR function. To test this hypothesis, we recently investigated the effect of microtubule disrupting agents (MIAs) or proinflammatory cytokines. These compounds are well-known inhibitors of GR transactivation property. MIAs activate c-Jun N-terminal kinase (JNK), which phosphorylates and inactivates GR, whereas proinflammatory cytokines, such as IL-6 or IL1beta, induce AP-1 or NF-kB activation, respectively, leading to GR inhibition. As expected, we observed that these molecules inhibit both CAR gene expression and phenobarbital-mediated CYP gene expression in human hepatocytes.