FUNCTION OF XENOBIOTIC RECEPTORS

AH受体(AHR)和过氧化物酶体增殖物激活受体α(PPARpha)是配体依赖的转录因子，已知能与外源化学物质结合并诱导靶基因表达。在啮齿动物模型系统中，它们的一些配体也是有效的非遗传毒性致癌物。这些受体的生理功能正在通过对空小鼠表型的研究来评估。AHR缺失和PPARα缺失的小鼠可以生育，但表现出不同严重程度的表型，这表明它们具有重要的功能和可能的内源性配体。由于免疫缺陷和组织纤维化，AHR缺失的小鼠通常健康状况不佳，特别是肝脏。在揭示AHR的作用机制方面已经取得了相当大的进展。由于维甲酸(RA)分解代谢缺陷，AHR缺失小鼠的肝脏中存在异常高水平的视黄酸(RA)，导致RAR反应基因的高水平表达，并由RAR控制的转谷氨酰胺酶II酶激活转化生长因子β(TGFβ)。这导致了TGFbeta刺激的发育过程中加速的细胞凋亡，以及由此导致的AHR缺失小鼠的小肝纤维化。这些数据表明，AHR对细胞周期控制有影响，并提示了某些AHR配体如2，4，7.8-四氯二苯并-对二恶英(TCDD)的毒性和致畸作用的可能机制。PPARα基因缺失的小鼠的表型比AHR基因缺失的小鼠严重得多。这些动物具有代谢脂肪酸的异常能力，这在某些饮食条件下尤其明显，会导致高血脂或饥饿。这些结果确立了PPARpha在生理动态平衡中的重要作用。PPARpha基因缺失的小鼠也能抵抗过氧化物酶增殖物诱导的肝癌发生。这在一定程度上是由于PPARpha对细胞周期控制的影响，并通过高水平表达过氧化物体酶酰辅酶A氧化酶来产生氧化应激，该酶产生副产物过氧化氢。对缺乏AHR和PPAR-α的小鼠的进一步研究应该会导致对这些受体的生理作用的更全面的理解，并为非遗传毒性致癌物的作用机制提供线索。-二恶英，过氧化物体增殖，受体，毒性，癌症易感性，

The Ah receptor (AHR) and peroxisome proliferator-activated receptor alpha (PPARalpha) are ligand-dependent transcription factors that are known to bind to xenobiotic chemicals and induce target gene expression. Some of their ligands are also potent non-genotoxic carcinogens in rodent model systems. The physiological functions of these receptors are being evaluated through the study of null mouse phenotypes. The AHR-null and PPARalpha-null mice are fertile but exhibit phenotypes varying severity suggesting that they have important functions and possible endogenous ligands. The AHR-null mice are generally in ill health due to an immune deficiency and tissue fibrosis, particularly in the liver. There has been considerable progress in unraveling the mechanism of AHR action. Livers of AHR-null mice have unusually high levels of retinoic acid (RA) due to a defect in RA catabolism which leads to high level expression of retinoic acid receptor (RAR) responsive genes and activation of transforming growth factor beta (TGFbeta) by the RAR-controlled transglutaminase II enzyme. This results in TGFbeta-stimulated accelerated apoptosis during development and the resultant small fibrotic livers of the AHR-null mice. These data indicate that AHR has an influence on cell cycle control and suggest a possible mechanism for the toxic and teratogenic effects of certain AHR ligands such as 2,4,7.8-tetrachlorodibenzo-p- dioxin (TCDD). The phenotype of the PPARalpha-null mice is considerable less severe than the AHR-null. These animals have an abnormal capacity to metabolize fatty acids which is particularly notable under certain dietary conditions leading to high serum lipids or starvation. These results establish an important role for PPARalpha in physiological homeostasis. PPARalpha null mice are also resistant to peroxisome proliferator-induced hepatocarcinogenesis. This is due in part to an effect of PPARalpha on cell cycle control and the production of oxidative stress through high level expression of the peroxisomal enzyme acyl-CoA oxidase that yields hydrogen peroxide as a byproduct. Further study of mice lacking AHR and PPAR-alpha should lead to a more complete understanding of the physiological roles of these receptors and clues to the mechanisms of action on non-genotoxic carcinogens. - Dioxin, Peroxisome proliferation, Receptors, Toxicity, Cancer susceptibility,