The kidney cytochrome P-4502C23 arachidonic acid epoxygenase is upregulated during dietary salt loading
The kidney cytochrome P-4502C23 arachidonic acid epoxygenase is upregulated during dietary salt loading
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DOI：
10.1172/jci7013
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发表时间：
1999-09-01
影响因子：
15.9
通讯作者：
Capdevila, JH
中科院分区：
文献类型：
--
作者：
Holla, VR;Makita, K;Capdevila, JH
膳食盐摄入过多会诱导肾脏花生四烯酸环氧化酶的活性，并显着增加其代谢物的尿排泄。环氧二十碳三烯酸是肾脏 P-450 花生四烯酸环氧化酶的产物，可抑制远端肾单位 Na+ 的重吸收。核酸杂交研究表明 P-450 2C23、2C24 和 2C11 的表达是主要的肾脏 2C 同工型，并且这些蛋白质缺乏显着的饮食盐依赖性转录调节。重组 P-450 2C11、2C23 和 2C24 催化花生四烯酸代谢为环氧酸和单羟基酸的混合物。虽然花生四烯酸酯 11,12-烯烃是 P-450 2C23 环氧化的首选目标（占总产物的 57%），但 P-450s 2C11 和 2C24 以几乎相同的效率环氧化 11,12-烯烃和 14,15-烯烃。立体化学比较表明，P-450 2C23 的区域化学和对映面选择性与肾微粒体环氧化酶相匹配，并且过量的膳食盐不会改变肾花生四烯酸环氧化酶的区域化学或立体化学选择性。使用针对重组 P-450 2C11 和 2C23 的抗体进行的抑制和免疫电泳实验表明，P-450 2C23 是大鼠肾脏中主要的 2C 花生四烯酸环氧化酶，并且肾 P-450 亚型受过量饮食盐摄入的调节。
Excess dietary salt intake induces the activity of the kidney arachidonate epoxygenase and markedly increases the urinary excretion of its metabolites. The epoxyeicosatrienoic acids, products of the kidney P-450 arachidonate epoxygenase, inhibit distal nephron Na+ reabsorption. Nucleic acid hybridization studies demonstrated the expression of P-450s 2C23, 2C24, and 2C11 as the predominant kidney 2C isoforms and the lack of significant dietary salt-dependent transcriptional regulation of these proteins. Recombinant P-450s 2C11, 2C23, and 2C24 catalyze arachidonate metabolism to mixtures of epoxy- and monohydroxylated acids. Whereas the arachidonate 11,12-olefm was the preferred target for epoxidation by P-450 2C23 (57% of total products), P-450s 2C11 and 2C24 epoxidized the 11,12-olefins and 14,15-olefins with nearly equal efficiency. Stereochemical comparisons demonstrated that the regiochemical and enantiofacial selectivity of P-450 2C23 matched that of the kidney microsomal epoxygenase and that excess dietary salt does not alter the regiochemical or stereochemical selectivity of the kidney arachidonate epoxygenase. Inhibition and immunoelectrophoresis experiments using antibodies raised against recombinant P-450s 2C11 and 2C23 demonstrated that P-450 2C23 is the major 2C arachidonic acid epoxygenase in the rat kidney and the renal P-450 isoform regulated by excess dietary salt intake.