FUNCTION OF XENOBIOTIC RECEPTORS

Ah受体（AHR）反式激活CYP 1A 1、CYP 1A 2和CYP 1B 1 基因和其他一些靶基因与二恶英复合后， 或多环芳烃。它被认为是介导毒性的 以及这些化学物质的致癌作用生理功能 目前尚不清楚AHR的存在，因为存在内源性 配体。确定AHR在发育和生理中的作用 在二恶英的生物学效应中，AHR基因敲除小鼠 生成的.在AHR缺失小鼠中观察到的表型表明， 受体在哺乳动物发育中具有重要作用， 生理稳态肝脏明显不正常 肝纤维化和肝结构改变肝内容物 视黄酸（RA）及其主要贮存产物棕榈酸视黄酯， 发现与野生型相比，在AHR-无效中显著升高 小鼠还注意到视黄酸反应基因的增加。低 也发现RA代谢水平表明细胞色素P450 负责RA catastrophe的是AHR的控制。RA改变 可能导致肝脏和其他器官的纤维化。一 一类结构多样的化学物质，称为过氧化物酶体增殖剂 也与类固醇中的受体家族相互作用 受体超家族在青蛙和哺乳动物中发现了三种亚基， 命名为PPAR-alpha、PPAR-beta和PPAR-gamma。阿尔法形式是最 在肝脏中大量表达，并参与调节酶的作用 在脂肪酸催化剂中的作用已得到证实。许多过氧化物酶体 PPAR-alpha的增殖物或潜在配体也是啮齿类动物 肝致癌物。这一事实引起了监管机构的关注，因为 人类暴露于高血脂药物中， 化学工业中的杀菌剂三氯乙烯等 具有过氧化物酶体增殖活性的化学品， 在啮齿动物模型系统中的肝癌发生潜力。解决 PPAR-alpha的生理作用及其在毒性和 过氧化物酶体增殖物的致癌作用，PPAR-alpha-null小鼠 被生产出来。致癌作用生物测定，使用有效的实验 过氧化物酶体增殖剂Wy-14，643显示， 对肝癌发生具有抗性，表明受体介导 非遗传毒性致癌物过氧化物酶体的作用机制 扩散者。还发现无PPAR的小鼠对许多， 但并不是所有的毒性都在野生型小鼠中发现， 增塑剂邻苯二甲酸二（2-乙基）乙酯。

The Ah receptor (AHR) trans-activates the CYP1A1, CYP1A2 and CYP1B1 genes and a number of other target genes after complexing with dioxins or polycyclic aromatic hydrocarbon. It is beleived to mediate the toxic and carcinogenic effects of these chemicals. The physiological function of the AHR is currently unknown, as is the existence of an endogenous ligand. To determine the role of AHR in development and physiological homeostasis, and in the biological effect of dioxins, AHR-null mice were generated. The phenotypes observed in AHR-null mice suggest that the receptor has an important role in mammalian development and physiological homeostasis. The liver is clearly not normal with evidence of fibrosis and altered hepatic architecture. Hepatic contents of retinoic acid (RA) and its major storage product, retinyl palmitate were found to be markedly elevated in the AHR-null compared to wild-type mice. An increase in retinoic acid-responsive genes was also noted. Low levels of RA metabolism was also found indicating that a cytochrome P450 responsible for RA catabolism is under control of the AHR. Altered RA levels may cause the fibrosis found in liver and other organs. A structurally-diverse class of chemicals called peroxisome proliferators also interact with a family of receptors that are in the steroid receptor superfamily. Three subunits are found in frogs and mammals, designated PPAR-alpha, PPAR-beta and PPAR-gamma. The alpha form is most abundantly expressed in liver and its role regulating enzymes involved in fatty acid catabolism has been demonstrated. A number of peroxisome proliferators or potential ligands for PPAR-alpha are also rodent hepatocarcinogens. This fact is of concern to regulatory agencies, since humans are exposed to hyperlipidemic drugs, plasticizers used in the chemical industry, the degreasing agent trichloroethylene and other chemicals exhibiting peroxisome proliferation activity and hepatocarcinogenesis potential in rodent model systems. To address the physiological role of PPAR-alpha and its role in the toxic and carcinogenic effects of peroxisome proliferators, PPAR-alpha-null mice were produced. A carcinogenesis bioassay using the potent experimental peroxisome proliferator Wy-14,643 revealed that PPAR-null mice were resistant to hepatocarcinogenesis indicating that the receptor mediates the mechanism of action of the non-genotoxic carcinogen peroxisome proliferators. PPAR-null mice were also found to be resistant to many, but not all of the toxicity's found in wild-type mice exposed to the plasticizer di(2-ethylhehyl)phthalate.