Xenobiotic Receptors

异生物素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。这是一种从体内清除化学物质的方法。然而，在许多情况下，外源性受体的刺激可导致作为异常靶基因激活的结果的毒性和致癌反应。实验室正在研究几种异戊糖受体。这些受体包括1）芳香烃受体（AHR）及其异源二聚化伴侣ARNT，其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）α、β和γ，其主要参与控制脂肪酸代谢和转运; 3）法尼醇X受体（FXR），其负责控制胆汁酸代谢和转运。这些受体的功能正在使用基因敲除小鼠进行评估。缺乏AHR的小鼠是可行的，但由于加速肝脏和其他器官纤维化而生病。对AHR缺失小鼠和源自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敲除揭示了该蛋白是AHR和缺氧诱导因子HIF-1 α的专性异源二聚化伴侣。还产生了缺氧诱导因子1 α（HNF-1 α）条件性无效小鼠。小鼠研究表明，PPARalpha是负责过氧化物酶体增殖剂的毒性作用，包括肝癌。这些研究导致了关于过氧化物酶体增殖物的作用机制和对这些化学品的反应的物种差异的假设，这对监管机构具有很大的价值。产生了PPARalpha-人源化小鼠，其揭示了受体蛋白是响应过氧化物酶体增殖物的物种差异的原因。PPARbeta参与免疫应答和细胞周期控制。最近的研究揭示了这种受体在调节结肠和皮肤癌发生中的作用。PPARgamma是脂肪形成、巨噬细胞功能控制所必需的，并且被认为是癌症修饰基因。最近的研究表明，该受体减弱化学致癌作用。发现FXR控制胆汁酸稳态和胆汁的肠肝流动，这是从体内消除许多废物分子所需的。这种受体的调节可能提供一种新的手段来控制胆固醇水平。胆汁酸也被认为是结肠癌发生的有效肿瘤促进剂。

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.