Wei P, Zhang J, Egan-Hafley M, Liang S, Moore D D
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature. 2000 Oct 19;407(6806):920-3. doi: 10.1038/35038112.
Organisms encounter a wide range of foreign compounds--or 'xenobiotics'--with potentially harmful consequences. The cytochrome P450 (CYP) enzymes metabolize xenobiotics and thus are a primary defence against these compounds. Increased expression of specific CYP genes in response to particular xenobiotics is a central component of this defence, although such induction can also increase production of toxic metabolites. Here we show that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the 'phenobarbital-like inducers'. The strong activation of Cyp2b10 gene expression by phenobarbital, or by the more potent TCPOBOP, is absent in mice lacking the CAR gene. These animals also show decreased metabolism of the classic CYP substrate zoxazolamine and a complete loss of the liver hypertrophic and hyperplastic responses to these inducers. Cocaine causes acute hepatotoxicity in wild-type mice previously exposed to phenobarbital-like inducers and this toxicity is also absent in the CAR-deficient animals. Thus, loss of CAR function alters sensitivity to toxins, increasing or decreasing it depending on the compound. Modulation of CAR activity in humans may significantly affect metabolism of drugs and other xenobiotics.
生物体接触到种类繁多的外来化合物（即“异生素”），这些化合物可能会带来有害后果。细胞色素P450（CYP）酶可代谢异生素，因此是抵御这些化合物的主要防线。特定CYP基因因特定异生素而表达增加，是这种防御机制的核心组成部分，尽管这种诱导也可能增加有毒代谢产物的生成。我们在此表明，核受体CAR介导了一类被称为“苯巴比妥样诱导剂”的异生素所引发的反应。在缺乏CAR基因的小鼠中，苯巴比妥或更强效的TCPOBOP对Cyp2b10基因表达的强烈激活作用消失。这些动物对经典CYP底物唑拉西泮的代谢也有所减少，并且对这些诱导剂的肝脏肥大和增生反应完全丧失。可卡因会在先前接触过苯巴比妥样诱导剂的野生型小鼠中引发急性肝毒性，而这种毒性在缺乏CAR的动物中同样不存在。因此，CAR功能的丧失会改变对毒素的敏感性，根据化合物的不同而增加或降低敏感性。调节人类体内CAR的活性可能会显著影响药物和其他异生素的代谢。
