Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12208-13. doi: 10.1073/pnas.95.21.12208.
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 16alpha-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.
核受体通过对关键代谢酶基因表达进行适当改变来响应环境变化，从而调节代谢途径。在此，基于迭代构建的核受体隐马尔可夫模型的计算搜索方法被用于鉴定一种在肝脏和肠道中表达的人类核受体，称为hPAR。发现hPAR可被孕烷以及包括利福平在内的临床使用药物有效激活，利福平是一种已知可选择性诱导人类而非小鼠CYP3A表达的抗生素。CYP3A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药物。有趣的是，hPAR不被孕烯醇酮16α-腈激活，孕烯醇酮16α-腈是小鼠CYP3A基因的强效诱导剂和小鼠受体PXR.1的激活剂。此外，发现hPAR通过人类而非小鼠CYP3A基因中存在的保守调控序列进行结合和反式激活。这些结果提供了证据，表明hPAR和PXR.1可能代表来自不同物种的直系同源基因，它们已经进化为响应药理学上不同的CYP3A激活剂来调节重叠的靶基因，并且对体外鉴定对人类重要的药物相互作用具有潜在意义。
