Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital
Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital
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DOI：
10.1124/mol.61.1.1
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发表时间：
2002-01-01
影响因子：
3.6
通讯作者：
Negishi, M
中科院分区：
文献类型：
--
作者：
Ueda, A;Hamadeh, HK;Negishi, M
苯巴比妥（PB）诱导各种基因编码药物/类固醇代谢酶，如细胞色素P450（P450）和转移酶。虽然核孤儿组成型活性受体（CAR）已被确定为调控CYP 2B诱导的关键转录因子，但CAR调控基因的全部范围仍然是一个主要问题。为此，采用逆转录酶-聚合酶链反应和cDNA微阵列技术来检查野生型和CAR缺失小鼠中的基因表达。结果表明，共检测到138个基因响应于PB处理而被诱导或抑制，其中约一半处于CAR调控下。包括CYP 2B 10、CYP 3A 11和NADPH-CoA还原酶，CAR调节一组PB诱导的药物/类固醇代谢酶。酶如氨基乙酰丙酸合酶I和角鲨烯环氧酶显示出PB的CAR非依赖性诱导。Cyp 4a 10和Cyp 4a 14代表仅在CAR-null小鼠中由PB诱导的基因组，表明CAR可能是阻止这些基因被PB诱导的转录阻断剂。此外，编码参与基本生物过程（如能量代谢）的酶和蛋白质的基因组经历了PB的CAR依赖性抑制。因此，CAR似乎具有多种作用，作为正调节剂和负调节剂，在响应PB的肝脏基因的调节中，除了药物/类固醇代谢之外。
Phenobarbital (PB) induces various gene encoding drug/ steroid-metabolizing enzymes such as cytochromes P450 (P450s) and transferases. Although the nuclear orphan constitutive active receptor (CAR) has been identified as a key transcription factor that regulates the induction of CYP2B, the full scope of CAR-regulated genes still remains a major question. To this end, reverse transcriptase-polymerase chain reaction and cDNA microarray techniques were employed to examine gene expression in wild-type and CAR-null mice. The results show that a total of 138 genes were detected to be either induced or repressed in response to PB treatment, of which about half were under CAR regulation. including CYP2B10, CYP3A11, and NADPH-CYP reductase, CAR regulated a group of the PB-induced drug/steroid-metabolizing enzymes. Enzymes such as amino levulinate synthase I and squalene epoxidase displayed CAR-independent induction by PB. Cyp4a10 and Cyp4a14 represented the group of genes induced by PB only in CAR-null mice, indicating that CAR may be a transcription blocker that prevents these genes from being induced by PB. Additionally, the group of genes encoding enzymes and proteins involved in basic biological processes such as energy metabolism underwent the CAR-dependent repression by PB. Thus, CAR seems to have diverse roles, both as a positive and negative regulator, in the regulation of hepatic genes in response to PB beyond drug/steroid metabolism.