Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor
Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor
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DOI：
10.1124/mol.62.2.359
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发表时间：
2002-08-01
影响因子：
3.6
通讯作者：
Liddle, C
中科院分区：
文献类型：
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作者：
Goodwin, B;Hodgson, E;Liddle, C
细胞色素P450 3A4(CYP3A4)是在成人肝脏中主要表达的P450，由多种结构不同的外源化学物质组成表达和转录激活。在这项研究中，我们研究了构成雄烷受体(CAR)在CYP3A4转录调控中的作用。CAR是类固醇/维甲酸/甲状腺激素受体超家族的成员。在此，我们证明了CAR能够在体外和体内反式激活CYP3A4基因的表达。CYP3A4的诱导依赖于基因启动子近端区域内的元件与远端异种生物反应增强子模块之间的协同作用。CAR的反应性主要由两个高亲和力结合基序介导，它们位于CYP3A4基因5‘侧翼区，位于转录起始点上游约7720和150个碱基。重要的是，人类CAR反应元件也介导了人类孕烷X受体对CYP3A4的反式激活，表明这些受体之间的相互作用可能是CYP3A4表达的一个重要决定因素。
Cytochrome P450 3A4 (CYP3A4), the predominant P450 expressed in adult human liver, is both constitutively expressed and transcriptionally activated by a variety of structurally diverse xenochemicals. In this study, we examined the role of the constitutive androstane receptor (CAR), a member of the steroid/retinoid/ thyroid hormone receptor superfamily, in the transcriptional regulation of CYP3A4. Herein, we demonstrate that CAR is capable of trans-activating expression of the CYP3A4 gene, both in vitro and in vivo. Induction of CYP3A4 is dependent on cooperativity between elements within the promoter proximal region of the gene and the distal xenobiotic-responsive enhancer module. CAR responsiveness was shown to be primarily mediated by two high-affinity binding motifs located within the CYP3A4 gene 5'-flanking region, approximately 7720 and 150 bases upstream of the transcription initiation site. Importantly, the human CAR response elements also mediate trans-activation of CYP3A4 by the human pregnane X receptor, suggesting that interplay between these receptors is likely to be an important determinant of CYP3A4 expression.