7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor
7-ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor
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DOI：
10.1074/jbc.m005988200
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发表时间：
2001-02-02
影响因子：
4.8
通讯作者：
Casper, RF
中科院分区：
文献类型：
--
作者：
Savouret, JF;Antenos, M;Casper, RF
我们已经确定7-酮胆固醇(7-KC)是一种内源性调节剂，通过与异种配体的竞争结合来抑制芳烃受体(AhR)的反式激活。7-KC与AhR结合，取代标记的二恶英(2，3，7，8-四氯二苯并(P)二恶英(TCDD))。体内IC50为5×10(-7)M，体外IC50为7×10(-6)M。这些数字与其在人体血浆和组织中的浓度一致。与7-KC结合可阻止AhR与DNA结合。7-KC阻断TCDD介导的T47-D细胞中稳定表达的报告基因结构的反式激活，以及内源性CyP1A1基因在HepG2细胞和原代猪主动脉内皮细胞中的表达。大鼠注射7-KC可阻断心肌血管内皮细胞中CYP 1A1信使RNA和蛋白的诱导。哺乳动物对AhR配体，特别是二恶英(TCDD)毒性作用的不同敏感性与7-羟基胆固醇脱氢酶的表达有关，7-羟基胆固醇脱氢酶是从7-羟基胆固醇合成7-KC的。已有文献记载AhR配体通过脂质过氧化和内皮功能障碍参与心血管疾病，现在可以在这种保护性调节剂置换的背景下进行研究。
We have identified 7-ketocholesterol (7-KC) as an endogenous modulator that inhibits transactivation by the arylhydrocarbon receptor (AhR) through competitive binding against xenobiotic ligands. 7-KC binds AhR and displaces labeled dioxin (2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD)). IC50 is 5 x 10(-7) M in vivo and 7 x 10(-6) M in vitro. These figures are consistent with its concentration in human blood plasma and tissues. Association with 7-KC prevents AhR binding to DNA. 7-KC blocks the TCDD-mediated transactivation of stably expressed reporter gene constructs in T47-D cells as well as the expression of the endogenous CYP 1A1 gene in HepG2 cells and in primary porcine aortic endothelial cells. Injection of 7-KC to rats blocks the induction of CYP 1A1 messenger RNA and protein in endothelial cells from myocardial blood vessels. The differential sensitivity of mammalian species to toxic effects of AhR ligands, especially dioxin (TCDD), correlates with the expression of 7-hydroxycholesterol dehydrogenase, which synthesizes 7-KC from 7-hydroxycholesterol. The documented involvement of AhR ligands in cardiovascular diseases through lipid peroxidation and endothelium dysfunction can now be examined in the context of displacement of this protective modulator.