Aryl hydrocarbon or dioxin receptor: biologic and toxic responses.
Aryl hydrocarbon or dioxin receptor: biologic and toxic responses.
复制标题
DOI：
10.1007/bfb0030908
复制
发表时间：
1994-01-01
期刊：
影响因子：
--
通讯作者：
Bock, K W
中科院分区：
文献类型：
--
作者：
Bock, K W
1. AhR代表配体激活的转录因子。受体激动剂包括平面芳香化合物、各种杂环植物成分和多氯二苯并对二恶英/多氯二苯并呋喃。后者由于其强结合亲和力和在人血液和脂肪中超过10年的长生物半衰期而导致受体的持续活化。实际上，地球上的每个人都通过饮食（> 90%）和母乳中的高浓度暴露于这些化合物。过去，多氯二苯并对二恶英/多氯二苯并呋喃在接触人群中产生了毒性反应（主要是氯痤疮和免疫抑制）。然而，目前一般人群中的多氯二苯并对二恶英/多氯二苯并呋喃水平（基础水平）低于引起毒理学关注的水平。2. AhR是一种螺旋-环-螺旋转录因子，与果蝇的发育基因sim和per相关。该受体的胞质形式作为与HSP 90的两个亚基的非活性复合物存在。在配体结合后，HSP 90被释放，受体作为异二聚体与相关蛋白ARNT一起进入细胞核。它以高亲和力结合几个基因上游区域的某些增强子元件，如细胞色素P4501 A1（CYP 1A 1）。AhR转录激活参与生长/分化的几种药物代谢酶和蛋白质，如纤溶酶原激活物抑制剂派-2和IL-1 β。此外，它还调节许多其他核转录因子的作用，如类固醇激素受体超家族的受体和细胞表面受体如EGF。除了CYP 1A 1的诱导，很少有人知道的AhR控制的基因的转录激活机制。许多AhR调节的生物反应（如雌激素和EGF受体的调节）似乎是间接的。3. AhR的持续激活可能是实验动物和人类毒性反应的原因。它们具有明显的组织和物种特异性。在啮齿动物中，对消耗综合征、免疫抑制、致畸性、氯痤疮和致癌性/促肿瘤性进行了充分研究。有很好的证据表明，AhR参与了这些反应。然而，从受体激活到各种毒性终点的事件链在很大程度上是未知的。上皮组织生长和分化的改变可能是大多数毒性反应的基础。已经取得了很多成就，主要是通过表征AhR和CYP 1A 1的转录激活。还有更多的工作摆在我们面前，例如，阐明AhR的生理作用和从受体激活到各种生物和毒性终点的事件链。
1. The AhR represents a ligand-activated transcription factor. Receptor agonists include planar aromatic compounds, a variety of heterocyclic plant constituents, and PCDD/PCDF. The latter lead to persistent activation of the receptor due to their strong binding affinity and long biologic half-life of over 10 years in human blood and fat. Practically every person on earth is exposed to these compounds via the diet (> 90%) and by high concentrations in mother's milk. PCDD/PCDF produced toxic responses in exposed people (primarily chloracne and immunosuppression) in the past. However, the present PCDD/PCDF levels (basal levels) in the general population are below those warranting toxicologic concern. 2. The AhR has been characterized as a helix-loop-helix transcription factor related to the Drosophila developmental genes sim and per. The cytosolic form of the receptor is present as an inactive complex with two subunits of HSP90. After ligand binding HSP90 is released and the receptor enters the nucleus as a heterodimer together with a related protein ARNT. It binds with high affinity to certain enhancer elements in the upstream region of several genes such as cytochrome P4501A1 (CYP1A1). The AhR transcriptionally activates several drug-metabolizing enzymes and proteins involved in growth/differentiation, such as the plasminogen activator inhibitor PAI-2 and IL-1 beta. In addition, it modulates the action of a number of other nuclear transcription factors such as receptors of the steroid hormone receptor superfamily and of cell surface receptors such as EGF. With the exception of CYP1A1 induction, little is known about the mechanism of transcriptional activation of the AhR-controlled genes. Many AhR-modulated biologic responses (such as modulation of the estrogen and EGF receptor) appear to be indirect. 3. Persistent activation of the AhR is probably responsible for toxic responses in experimental animals and humans. They are markedly tissue and species specific. In rodents a wasting syndrome, immunosuppression, teratogenicity, chloracne, and carcinogenicity/tumor promotion have been well studied. There is good evidence for an involvement for the AhR in these responses. However, the chain of events from receptor activation to the diverse toxic endpoints is largely unknown. Alteration of growth and differentiation of epithelial tissues may underlie most of the toxic responses. A lot has already been achieved, mostly by characterizing the AhR and transcriptional activation of CYP1A1. Still more work lies ahead of us, for example, elucidation of the physiologic roles of the AhR and of the chains of events from receptor activation to the various biologic and toxic endpoints.