Savouret J F, Antenos M, Quesne M, Xu J, Milgrom E, Casper R F
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
J Biol Chem. 2001 Feb 2;276(5):3054-9. doi: 10.1074/jbc.M005988200. Epub 2000 Oct 20.
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)). IC(50) 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.
我们已确定7-酮胆固醇（7-KC）是一种内源性调节剂，它通过与外源性配体竞争性结合来抑制芳烃受体（AhR）的反式激活。7-KC与AhR结合并取代标记的二恶英（2,3,7,8-四氯二苯并对二恶英（TCDD））。体内半数抑制浓度（IC50）为5×10⁻⁷mol/L，体外为7×10⁻⁶mol/L。这些数值与其在人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可阻断TCDD介导的T47-D细胞中稳定表达的报告基因构建体的反式激活，以及HepG2细胞和原代猪主动脉内皮细胞中内源性CYP 1A1基因的表达。给大鼠注射7-KC可阻断心肌血管内皮细胞中CYP 1A1信使核糖核酸和蛋白质的诱导。哺乳动物物种对AhR配体尤其是二恶英（TCDD）毒性作用的不同敏感性，与7-羟基胆固醇脱氢酶的表达相关，该酶可从7-羟基胆固醇合成7-KC。现在可以在这种保护性调节剂被取代的背景下，研究AhR配体通过脂质过氧化和内皮功能障碍在心血管疾病中的作用。
