THE AH RECEPTOR - MEDIATOR OF THE TOXICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) AND RELATED-COMPOUNDS
THE AH RECEPTOR - MEDIATOR OF THE TOXICITY OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) AND RELATED-COMPOUNDS
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DOI：
10.1016/0378-4274(94)90139-2
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发表时间：
1994-01-01
影响因子：
3.5
通讯作者：
HARPER, PA
中科院分区：
文献类型：
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作者：
OKEY, AB;RIDDICK, DS;HARPER, PA
过去15年的大量研究表明，在实验室动物中，Ah（芳烃）受体（AhR）介导了卤代芳烃（如多氯二苯并对二恶英、多氯二苯并呋喃和多卤代联苯）的大多数（如果不是全部的话）毒性作用。最近，AhR已被证明也存在于各种人体组织和人体细胞系中。一般来说，人类的AhR似乎与啮齿动物的AhR功能非常相似。然而，有毒的HAH如2，3，7，8-四氯二苯并-对-二恶英与来自人类来源的AhR结合的亲和力通常低于这些HAH与来自啮齿动物组织的Ah受体结合的亲和力。这种较低的亲和力可以部分解释为什么人类物种似乎比许多实验室动物对HAH的影响不那么敏感。AhR增强CYP 1A亚家族中编码细胞色素P450酶的基因的转录，但大多数HAH的毒性作用似乎不需要P450诱导本身。最近对HAH毒性机制的分子研究表明，AhR也可能介导其他几个基因的表达，包括调节细胞生长和分化的基因。尽管已知被HAH改变的细胞反应的库不断扩大（可能通过AhR），但尚不清楚哪些AhR介导的作用是HAH毒性的关键事件。在过去的一年中，AhR的两个亚基已经被克隆;这种克隆，沿着其他分子研究，应该大大扩大我们的机会，以了解具体的机制和途径，HAH引起毒性。
A considerable body of research over the past fifteen years establishes that in laboratory animals the Ah (aromatic hydrocarbon) receptor (AhR) mediates most, if not all, toxic effects of halogenated aromatic hydrocarbons such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and polyhalogenated biphenyls. More recently the AhR has been shown to also exist in a wide variety of human tissues and human cell lines. In general the AhR in humans appears to function very much like the AhR in rodents. However, the affinity with which toxic HAHs such as 2,3,7,8-tetrachlorodibenzo-p-dioxin bind to the AhR from human sources generally is lower than the affinity with which these HAHs bind to the Ah receptors from rodent tissues. This lower affinity may explain, in part, why the human species seems less sensitive than many laboratory animals to the effects of HAHs. The AhR enhances transcription of genes encoding cytochrome P450 enzymes in the CYP1A subfamily, but most of the toxic effects of HAHs do not seem to require P450 induction per se. Recent molecular approaches to the mechanism of HAH toxicity indicate that the AhR also may mediate expression of several other genes, including genes that regulate cell growth and differentiation. Despite the expanding repertoire of cellular responses known to be altered by HAHs (potentially through the AhR) it is not yet clear which AhR-mediated actions are the key events in HAH toxicity. Within the past year two subunits of the AhR have been cloned; this cloning, along with other molecular investigations, should greatly expand our opportunity to understand the specific mechanisms and pathways by which HAHs cause toxicity.