Xenobiotic Receptors

异源生物受体介导生物体对其化学环境的反应。一般的范例是，化学物质进入细胞并与受体结合，导致编码代谢化学物质的酶的基因激活。这是一种从体内清除化学物质的方法。然而，在许多情况下，由于靶基因的异常激活，外源受体的刺激可以导致毒性和致癌反应。几种异生受体正在实验室中进行研究。这些受体包括1)芳香烃受体(AHR)及其异二聚化伙伴ARNT，它们介导对二恶英和多卤代烃的毒性反应；2)过氧化物酶体增殖物激活受体(PPAR)，主要参与控制脂肪酸的代谢和运输；3)法尼类X受体(FXR)，负责控制胆汁酸的代谢和运输。这些受体的功能正在用基因敲除小鼠进行评估。缺乏AHR的小鼠是存活的，但由于肝脏和其他器官纤维化加速而患病。对AHR缺失的小鼠和从这些小鼠衍生的细胞系的研究揭示了AHR在细胞周期控制中的作用。Arnt基因敲除表明该蛋白是AHR和缺氧诱导因子HIF-1α的专有异二聚化伙伴。低氧诱导因子1α(HNF-1α)条件性空白小鼠也已产生。Null小鼠研究表明，PPARpha负责过氧化物体增殖物的毒性效应，包括肝癌的发生。这些研究导致了关于过氧化物体增殖物的作用机制以及对这些化学物质的反应的物种差异的假说，这将对监管机构具有重要的价值。一只PPARpha人源化的小鼠被制造出来，揭示了受体蛋白是导致对过氧化物体增殖物反应的物种差异的原因。PPARbeta参与免疫反应和细胞周期控制。最近的研究揭示了这种受体在调节结肠癌和皮肤癌发生中的作用。PPARGamma是脂肪生成、巨噬细胞功能控制所必需的，被认为是一种癌症修饰基因，最近的研究表明，这种受体可以减弱化学致癌作用。FXR被发现控制胆汁酸的动态平衡和胆汁的肝-肠流动，这是从体内清除许多废物分子所必需的。这种受体的调节可能会提供一种控制胆固醇水平的新方法。胆汁酸也被认为是结肠癌发生的有效促癌剂。

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 farnesoid 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. Hypoxia-inducible factor 1alpha (HNF-1alpha) conditional null mice have also been generated. 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. A PPARalpha-humanized mouse was produced that revealed that the receptor protein is responsible for the species differences in response to peroxisome proliferators. PPARbeta is involved in the immune response and in cell cycle control. Recent studies revealed a role for this receptor in modulating colon and skin carcinogenesis. PPARgamma is required for adipogenesis, control of macrophage function and is thought to be a cancer modifier gene, Recent studies revealed that this receptor attenuates chemical carcinogenesis. 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. Bile acids are also believed to be potent tumor promoters for colon carcinogenesis.