FUNCTION OF XENOBIOTIC RECEPTORS

异生物受体的功能

• 批准号: 6160954
• 负责人: F J GONZALEZ
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160954
• 关键词: aromatic hydrocarbon receptor; chemical carcinogen; chemical carcinogenesis; cytochrome P450; developmental genetics; dioxins; drug metabolism; enzyme induction /repression; laboratory mouse; liver; liver metabolism; peroxisome; protein isoforms; species difference; transcription factor

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.

AH受体(AHR)反式激活细胞色素P1A1、细胞色素P1A2和细胞色素P1B1 与二恶英络合后的基因和其他一些靶基因 或多环芳烃。它被认为是调解有毒物质的 以及这些化学物质的致癌作用。生理功能 目前尚不清楚AHR是否存在内源性 莱兰德。确定AHR在发育和生理过程中的作用 在二恶英的生物效应中，AHR基因缺失的小鼠 已生成。在AHR缺失小鼠中观察到的表型表明 受体在哺乳动物的发育和发育中起重要作用 生理动态平衡。有证据表明，肝脏明显不正常 肝纤维化和肝脏结构改变。肝脏内容物 维甲酸(RA)及其主要储藏产物--维甲酸棕榈酸酯 发现与野生型相比，AHR-Null显著升高 老鼠。维甲酸反应基因的增加也被注意到。低 RA代谢水平也表明细胞色素P450 负责RA分解代谢的是由AHR控制的。更改的RA 水平可能会导致肝脏和其他器官的纤维化。一个 一类结构多样的化学物质，称为过氧化物酶增殖物 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个亚基， 指定为PPAR-α、PPAR-β和PPAR-伽马。字母形式是最多的 肝脏中的丰富表达及其调控酶的作用 在脂肪酸的分解代谢中已经被证明。一些过氧酶体 PPAR-α的增殖物或潜在配体也是啮齿动物 致癌物质。这一事实引起了监管机构的关注，因为 人类接触到高血脂药物，用于治疗的增塑剂 化工、三氯乙烯等脱脂剂 表现出过氧化物酶体增殖活性和 啮齿动物模型系统中的肝癌发生潜能。要解决这个问题 PPAR-α的生理作用及其在中毒性和慢性阻塞性肺疾病中的作用 过氧化物酶体增殖物对PPARα缺失小鼠的致癌作用 被生产出来了。一种有效的实验致癌生物测定方法 过氧化物酶体增殖剂Wy-14,643显示PPAR缺失的小鼠 对肝癌发生的抵抗表明该受体介导 非遗传毒性致癌物过氧化物体的作用机制 扩散者。PPAR缺失的小鼠也被发现对许多， 但并不是所有的毒性都在暴露于 增塑剂邻苯二甲酸二乙酯。