Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region.
Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region.
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组成型雄甾烷受体通过 5 侧翼区域中的共同调节元件转录激活人类 CYP1A1 和 CYP1A2 基因。
DOI：
10.1016/j.bcp.2009.08.008
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发表时间：
2010
影响因子：
5.8
通讯作者：
Y. Yamazoe
中科院分区：
文献类型：
--
作者：
K. Yoshinari;Noriaki Yoda;T. Toriyabe;Y. Yamazoe
长期以来，苯巴比妥可能通过一条不依赖芳烃受体的途径(S)增加细胞内细胞色素P1A1和细胞色素P1A2的水平。我们研究了构成雄烷受体(CAR)在人类细胞色素P1A1和细胞色素P1A2反式激活中的作用。这些基因以头对头的方式定位，共享一个5‘侧翼区域。因此，使用包含两个不同报告基因之间的全部或部分缺失的人类CYP1A启动子的双报告构建物进行报告分析。在该系统中，人CAR(Hcar)通过−461至−554和−18089至−21975的共同启动子区域增强了这两个基因的转录。通过使用额外的缺失和突变构建体的报告分析、凝胶迁移率改变分析和染色质免疫沉淀分析，位于−1A1的520左右的ER8基序(由8个核苷酸分隔的外翻重复序列)被鉴定为HCAR反应元件和HCAR/人视黄酸X受体α异源二聚体的结合基序。在芳香烃受体配体存在的情况下，HCAR也增强了这两个基因的转录。最后，Hcar的激活增加了培养的人肝细胞中的细胞色素P1A1和细胞色素P1A2的mRNA水平。我们的结果表明，CAR通过共同的顺式元件ER8反式激活人肝细胞中的细胞色素P1A1和细胞色素P1A2。有趣的是，ER8基序在不同物种的CYP1A1近端启动子序列中高度保守，表明CAR在异物诱导的CYP1A1和CYP1A2的表达中发挥了基础作用，而不依赖于芳烃受体。
Phenobarbital has long been known to increase cellular levels of CYP1A1 and CYP1A2 possibly through a pathway(s) independent of aryl hydrocarbon receptor. We have investigated the role of constitutive androstane receptor (CAR), a xenobiotic-responsive nuclear receptor, in the transactivation of human CYP1A1 and CYP1A2. These genes are located in a head-to-head orientation, sharing a 5′-flanking region. Reporter assays were thus performed with dual-reporter constructs, containing the whole or partially deleted human CYP1A promoter between two different reporter genes. In this system, human CAR (hCAR) enhanced the transcription of both genes through common promoter regions from −461 to −554 and from −18089 to −21975 of CYP1A1. With reporter assays using additional deleted and mutated constructs, electrophoresis mobility shift assays and chromatin immunoprecipitation assays, an ER8 motif (everted repeat separated by eight nucleotides), located at around −520 of CYP1A1, was identified as an hCAR-responsive element and a binding motif of hCAR/human retinoid X receptor α heterodimer. hCAR enhanced the transcription of both genes also in the presence of an aryl hydrocarbon receptor ligand. Finally, hCAR activation increased CYP1A1 and CYP1A2 mRNA levels in cultured human hepatocytes. Our results indicate that CAR transactivates human CYP1A1 and CYP1A2 in human hepatocytes through the common cis-element ER8. Interestingly, the ER8 motif is highly conserved in the CYP1A1 proximal promoter sequences of various species, suggesting a fundamental role of CAR in the xenobiotic-induced expression of CYP1A1 and CYP1A2 independent of aryl hydrocarbon receptor.
影响因子：
3.6
作者：
Kobayashi, K;Sueyoshi, T;Negishi, M
通讯作者：
Negishi, M
Hepa lclc7 细胞中光氧化色氨酸诱导细胞色素 P4501A1。
影响因子：
5.8
作者：
Sindhu,RK;Reisz-Porszasz,S;Hankinson,O;Kikkawa,Y
通讯作者：
Kikkawa,Y
苯妥英钠对两名患者血浆氯氮平浓度的影响。
DOI：
--
发表时间：
1991
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
Miller,DD
通讯作者：
Miller,DD