FUNCTION OF XENOBIOTIC RECEPTORS

异生物受体的功能

• 批准号: 2463675
• 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/2463675
• 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

P450s and other enzymes are under control of ligand-dependent transcription factors that interact with xenobiotics. The most well studied is the dioxin or Ah receptor that is composed of two heterodimeric subunits consisting of a ligand binding subunit (AHR) and a subunit called the Ah receptor nuclear translocator (Arnt). This AHR trans-activates the CYP1A1, CYP1A2 and CYP1B1 genes and a number of other genes after complexing with 2,3 ,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbon inducers. The physiological function of the Ah receptor, if any, 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 in even younger null mice with evidence of fibrosis and altered hepatic architecture. In older animals, defects were detected in the cardiovascular system, including heart hypertrophy. The immune system was also affect by the loss of the AHR. The AHR-null mice were used to determine the role of the receptor in acute toxicity of TCDD. The null animals were resistant to the thymic toxicity and wasting syndrome associated with this notorious environmental contaminant. 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 participation in regulating 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 hyperlipidemics, leukotriene antagonists and other drugs are peroxisome proliferators and are used in humans. To determine the physiological roles of xenobiotic receptors and P450s and their participation in the process o chemical carcinogenesis in an intact animal model, PPAR-alpha null mice were prepared and their phenotypes analyzed. These mice exhibited no phenotype suggesting an important role for the receptor in mammalian development. The null mice were completely resistant to all effects of peroxisome proliferators including induction of peroxisomes, target gene expression and hepatomegaly. Studies are in progress to determine the role of PPAR- alpha in the carcinogenic properties of peroxisome proliferators.

P450和其他酶受配体依赖性 与异生物质相互作用的转录因子。最完好的 研究的是二恶英或Ah受体，由两个 由配体结合亚基（AHR）组成的异二聚体亚基， 一种称为Ah受体核转运蛋白（Arnt）的亚基。这个AHR 反式激活CYP 1A 1、CYP 1A 2和CYP 1B 1基因， 与2，3，7，8-四氯二苯并-对-二恶英络合后的其他基因 （TCDD）或多环芳烃诱导剂。生理 Ah受体的功能，如果有的话，目前是未知的， 内源性配体的存在。确定AHR在以下方面的作用： 发展和生理稳态，并在生物效应 的二恶英，AHR-裸小鼠产生。观察到的表型 AHR基因敲除小鼠表明，该受体在 哺乳动物的发育和生理稳态。肝脏是 在有纤维化证据的更年轻的无效小鼠中明显不正常 和改变的肝脏结构在年老的动物中， 在心血管系统中检测到，包括心脏肥大。的 免疫系统也受到AHR丧失的影响。AHR缺失小鼠 用于确定受体在急性毒性中的作用， TCDD。无效动物对胸腺毒性具有抗性， 与这种臭名昭著的环境污染有关的 污染物一类结构多样的化学物质， 过氧化物酶体增殖物还与受体家族相互作用， 属于类固醇受体超家族三个亚基被发现在 青蛙和哺乳动物，命名为PPAR-alpha、PPAR-beta和PPAR-gamma。的 α型在肝脏中表达最丰富， 在调节脂肪酸代谢中的作用已被证实。一些 过氧化物酶体增殖物或潜在的PPAR-alpha配体，也 啮齿类动物肝癌原。这一事实引起了监管机构的关注。 自高血压病、白三烯拮抗剂和其他药物 是过氧化物酶体增殖剂并用于人类。确定 外源性受体和P450的生理作用及其 参与化学致癌过程， 制备动物模型，PPAR-alpha无效小鼠，并将其表型 分析了这些小鼠没有表现出表型，这表明了重要的 受体在哺乳动物发育中的作用。无效小鼠为 完全抵抗过氧化物酶体增殖剂的所有作用 包括过氧化物酶体的诱导、靶基因表达和 肝肿大研究正在进行中，以确定过氧化物酶体增殖物激活受体的作用- α在过氧化物酶体增殖物的致癌特性。