Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriureticeicosanoid, in human kidney - Role of CYP4F2 and CYP4A11

20-Hydroxyeicosatetraenoic acid (20-HETE), an omega-hydroxylated arachidoni c acid (AA) metabolite, elicits specific effects on kidney vascular and tub ular function that, in turn, influence blood pressure control. The human ki dney's capacity to convert AA to SO-METE is unclear, however, as is the und erlying P450 catalyst. Microsomes from human kidney cortex were found to co nvert AA to a single major product, namely 80-HETE, but failed to catalyze AA epoxygenation and midchain hydroxylation. Despite the monophasic nature of renal AA omega-hydroxylation kinetics, immunochemical studies revealed p articipation of two P450s, CYP4FS and CYP4A11, since antibodies to these en zymes inhibited SO-METE formation by 65.9 +/-17 and 32.5 +/- 14%, respectiv ely. Western blotting confirmed abundant expression of these CYP4 proteins in human kidney and revealed that other AA-oxidizing P450s, including CYP2C 8, CYP2C9, and CYP2E1, were not expressed. Immunocytochemistry showed CYP4F 2 and CYP4A11 expression in only the S2 and 53 segments of proximal tubules in cortex and outer medulla, Our results demonstrate that CYP4F2 and CYP4A 11 underlie conversion of AA to 20-METE, a natriuretic and vasoactive eicos anoid, in human kidney. Considering their proximal tubular localization, th ese P450 enzymes may partake in pivotal renal functions, including the regu lation of salt and water balance, and arterial blood pressure itself.