Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Mailstop 3014, 1095 Willowdale Rd, Morgantown, WV 26505, USA.
Expert Opin Drug Metab Toxicol. 2011 Oct;7(10):1267-93. doi: 10.1517/17425255.2011.614947. Epub 2011 Sep 2.
A key to understanding the biological function(s) of the aryl hydrocarbon receptor (AHR) - a xenobiotic-activated receptor - is to identify its endogenous ligand(s). The discovery of a tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) as an endogenous, high affinity agonist of AHR filled this knowledge gap in the context of skin physiology and pathology in response to light and opened several new directions for research on AHR.
This paper reviews major developments in the study of light-elicited AHR signaling and its impact on drug metabolism, skin physiology and disease with a focus on the identification of AHR ligands from Trp photoproducts and the AHR-mediated UV response. This review consists of material obtained from Medline and PubMed literature searches up to May 2011.
The recognition of FICZ as a potent, endogenous ligand of AHR provided a molecular link between light exposure and AHR signaling and function. The uncovering of the bifurcated signaling pathway of AHR in the mammalian UV response - that is, activation of the cytoplasmic AHR by light via FICZ leads to: i) AHR/AH response element-dependent transcription to induce CYP1A1 and ii) activation of the AHR-pp60(src)-EGFR pathway to induce Cox-2 - put forward a working model for the multiple roles of AHR in skin function and disease that include drug metabolism, circadian oscillation, melanogenesis, inflammation, immunosuppression and cancer. Such findings suggest AHR as a therapeutic target for cancer, autoimmune dysfunction, inflammatory disease and stem cell therapy.
理解芳基烃受体（AHR）——一种外源性激活受体——的生物学功能的关键是确定其内源性配体。色氨酸光产物 6-甲酰基吲哚并[3,2-b]咔唑（FICZ）作为 AHR 的内源性高亲和力激动剂的发现填补了皮肤生理学和病理学中对光的反应的这一知识空白，并为 AHR 的研究开辟了几个新方向。
本文综述了光诱导 AHR 信号及其对药物代谢、皮肤生理学和疾病影响的研究的主要进展，重点介绍了从色氨酸光产物中鉴定 AHR 配体和 AHR 介导的 UV 反应。这篇综述的材料来自于截至 2011 年 5 月的 Medline 和 PubMed 文献检索。
FICZ 作为 AHR 的有效内源性配体的发现为光暴露与 AHR 信号和功能之间提供了分子联系。哺乳动物 UV 反应中 AHR 的分叉信号通路的揭示——即光通过 FICZ 激活细胞质 AHR，导致：i）AHR/AH 反应元件依赖性转录以诱导 CYP1A1 和 ii）激活 AHR-pp60(src)-EGFR 途径以诱导 Cox-2——提出了 AHR 在皮肤功能和疾病中的多种作用的工作模型，包括药物代谢、昼夜节律振荡、黑色素生成、炎症、免疫抑制和癌症。这些发现表明 AHR 是癌症、自身免疫功能障碍、炎症性疾病和干细胞治疗的治疗靶点。
