Gonzalez F J, Fernandez-Salguero P
Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
Drug Metab Dispos. 1998 Dec;26(12):1194-8.
The aryl hydrocarbon receptor (AHR) is believed to mediate the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. AHR is a member of the Per, ARNT, Sim/basic-helix-loop-helix superfamily of ligand-activated transcription factors that also harbors the transcription factors involved in the hypoxia response, development of the central nervous system, and day-night adaptations. To investigate the role of AHR in chemical toxicity and carcinogenesis and to determine any possible function in mammalian development and physiological homeostasis, AHR-null mice were developed. The AHR-null mice were resistant to the acute toxicity of TCDD and had an altered teratogenic response to this compound. These mice were found to have a number of abnormal phenotypes, thus confirming that AHR plays an important developmental and physiological role. Among the most consistent phenotypes was an altered liver pathology that was associated with accelerated rates of apoptosis. Evidence suggests that this may be related to an abnormal accumulation of levels of hepatic retinoic acid that cause an activation of transforming growth factor beta, resulting in stimulation of apoptosis. AHR may directly or indirectly control levels of a cytochrome P450 that is responsible for catabolizing retinoic acid.
芳基烃受体（AHR）被认为可介导2,3,7,8-四氯二苯并对二恶英（TCDD）、多氯联苯和多环芳烃的毒性作用。AHR是Per、ARNT、Sim/碱性螺旋-环-螺旋超家族中配体激活转录因子的一员，该超家族还包含参与缺氧反应、中枢神经系统发育和昼夜适应的转录因子。为了研究AHR在化学毒性和致癌作用中的作用，并确定其在哺乳动物发育和生理稳态中的任何可能功能，人们培育出了AHR基因敲除小鼠。AHR基因敲除小鼠对TCDD的急性毒性具有抗性，并且对该化合物的致畸反应发生了改变。人们发现这些小鼠有许多异常表型，从而证实AHR发挥着重要的发育和生理作用。最一致的表型之一是肝脏病理改变，这与细胞凋亡加速有关。有证据表明，这可能与肝脏视黄酸水平的异常积累有关，视黄酸水平的异常积累会导致转化生长因子β的激活，从而刺激细胞凋亡。AHR可能直接或间接控制负责分解视黄酸的细胞色素P450的水平。
