Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction
Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction
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DOI：
10.1073/pnas.95.21.12208
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发表时间：
1998-10-13
影响因子：
11.1
通讯作者：
Berkenstam, A
中科院分区：
文献类型：
--
作者：
Bertilsson, G;Heidrich, J;Berkenstam, A
核受体通过适当改变关键代谢酶的基因表达来调节代谢途径，以响应环境的变化。在此，使用基于迭代构建的核受体隐马尔可夫模型的计算搜索方法来鉴定在肝脏和肠中表达的人核受体，称为hPAR。发现hPAR被孕烷和临床使用的药物（包括利福平，一种已知选择性诱导人而非鼠CYP 3A表达的抗生素）有效激活。CYP 3A药物代谢酶在肠道和肝脏中表达，以响应环境化学物质和临床使用的药物。有趣的是，hPAR不被双烯醇酮16 α-甲腈激活，双烯醇酮16 α-甲腈是鼠CYP 3A基因的有效诱导剂和小鼠受体PXR. 1的激活剂。此外，发现hPAR结合并通过存在于人而非鼠CYP 3A基因中的保守调控序列反式激活。这些结果提供的证据表明，hPAR和PXR. 1可能代表来自不同物种的正向同源基因，这些基因已经进化为调节重叠的靶基因，以响应不同的CYP 3A激活剂，并对体外鉴定对人类重要的药物相互作用具有潜在意义。
Nuclear receptors regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes, Here, a computational search approach based on iteratively built hidden Markov models of nuclear receptors was used to identify a human nuclear receptor, termed hPAR, that is expressed in liver and intestines. hPAR was found to be efficiently activated by pregnanes and by clinically used drugs including rifampicin, an antibiotic known to selectively induce human but not murine CYP3A expression. The CYP3A drug-metabolizing enzymes are expressed in gut and liver in response to environmental chemicals and clinically used drugs. Interestingly, hPAR is not activated by pregnenolone 16 alpha-carbonitrile, which is a potent inducer of murine CYP3A genes and an activator of the mouse receptor PXR.1. Furthermore, hPAR was found to bind to and trans-activate through a conserved regulatory sequence present in human but not murine CYP3A genes. These results provide evidence that hPAR and PXR.1 may represent orthologous genes from different species that have evolved to regulate overlapping target genes in response to pharmacologically distinct CYP3A activators, and have potential implications for the in vitro identification of drug interactions important to humans.