Margalit A, Hauser S D, Zweifel B S, Anderson M A, Isakson P C
Department of Pharmacology, Searle Research and Development, St. Louis, Missouri 63198, USA.
Am J Physiol. 1998 Feb;274(2):R294-302. doi: 10.1152/ajpregu.1998.274.2.R294.
Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitor L-buthionine-[S,R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.
给小鼠腹腔注射尿酸盐晶体，可在长达6小时内降低随后巨噬细胞将花生四烯酸（AA）转化为前列腺素（PGs）和12-羟基二十碳四烯酸的能力。相比之下，12-羟基十七碳三烯酸（12-HHT）的水平则显著升高。这种代谢特征先前在体外将重组环氧化酶（COX）与还原型谷胱甘肽（GSH）一起孵育时观察到。对腹腔GSH水平的分析显示，注射尿酸盐晶体后其水平升高了五倍。GSH合成抑制剂L-丁硫氨酸-[S,R]-亚砜亚胺部分逆转了尿酸盐晶体对GSH升高和PG合成的影响。此外，向分离的腹腔巨噬细胞中添加外源性GSH会使AA代谢从PGs转向12-HHT。注射尿酸盐晶体可降低COX-1水平，但诱导腹腔细胞中COX-2的表达。COX-1水平的降低可能在1至2小时后导致PG合成减弱，但在COX-2水平较高时，PG合成在长达6小时内仍受到抑制。总体而言，我们的结果表明，在该模型中升高的GSH水平会抑制PG的产生，并为GSH在PG生物合成调节中的作用提供了体内证据。
