Function of Xenobiotic Receptors

外源受体介导生物体对其化学环境的反应。一般的范式是，化学物质进入细胞并结合受体，导致编码代谢化学物质的酶的基因激活。这是一种消除体内化学物质的方法。然而，在许多情况下，由于靶基因异常激活，外源受体的刺激可导致毒性和致癌反应。几种异种受体正在实验室进行研究。其中包括：1)芳烃受体（AHR）及其异二聚化伙伴ARNT，介导二恶英和多卤代烃的毒性反应；2)过氧化物酶体增殖体激活受体(PPAR) α、β和γ，主要参与控制脂肪酸代谢和运输；3)法尼基X受体（FXR），负责控制胆汁酸代谢和运输。这些受体的功能正在用基因敲除小鼠进行评估。缺乏AHR的小鼠可以存活，但由于肝脏和其他器官纤维化加速而患病。对AHR缺失小鼠和来源于这些小鼠的细胞系的研究揭示了AHR在细胞周期控制中的作用。ARNT敲除表明该蛋白是AHR和缺氧诱导因子hif -1 α的专性异二聚化伙伴。无小鼠研究表明，ppar与过氧化物酶体增殖因子的毒性作用有关，包括肝癌的发生。这些研究对过氧化物酶体增殖体的作用机制和物种对这些化学物质的反应差异进行了假设，对监管机构具有重要价值。ppar β参与免疫反应和细胞周期控制。FXR被发现可以控制胆汁酸稳态和胆汁的肠肝流动，这是消除体内许多废物分子所必需的。调节这种受体可能提供一种控制胆固醇水平的新方法。

Xenobiotic receptors mediate the response of organisms to their chemical environment. The general paradigm is that chemicals enter the cell and bind receptors leading to the activation of genes that encode enzymes that metabolize the chemical. This is a means to eliminate chemicals from the body. However in many cases, stimulation of xenobiotic receptors can lead to toxic and carcinogenic responses as a result of abnormal target gene activation. Several xenobitoic receptors are under study in the laboratory. These include 1) the aryl hydrocarbon receptor (AHR) and its heterodimerization partner ARNT that mediate the toxic response to dioxins and polyhalogenated hydrocarbons 2) the peroxisome proliferator activated receptors (PPAR) alpha, beta and gamma that are mainly involved in control of fatty acid metabolism and transport, 3) the farnesyl X receptor (FXR) that is responsible for control of bile acid metabolism and transport. The function of these receptors is being evaluated using gene knockout mice. Mice lacking the AHR are viable but are sick due to accelerated liver and other organ fibrosis. Studies with the AHR-null mice and cell lines derived from these mice have revealed a role for the AHR in cell cycle control. The ARNT knockout revealed that this protein is an obligate heterodimerization partner of the AHR and the hypoxia inducible factor HIF-1alpha. Null mouse studies revealed that the PPARalpha is responsible for the toxic effects of peroxisome proliferators including hepatocarcinogenesis. These studies have led to hypothesis on the mechanism of action of peroxisome proliferators and the species differences in response to these chemicals that will be of great value to regulatory agencies. PPARbeta is involved in the immune response and in cell cycle control. The FXR was found to control bile acid homeostasis and the enterohepatic flow of bile that is required for the elimination of many waste molecules from the body. Modulation of this receptor may offer a novel means to control cholesterol levels.