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Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation

Item Type:Article
Title:Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation
Creators Name:Mueller, D.N. and Schmidt, C. and Barbosa-Sicard, E. and Wellner, M. and Gross, V. and Hercule, H. and Markovic, M. and Honeck, H. and Luft, F.C. and Schunck, W.H.
Abstract:Arachidonic acid (AA) hydroxylation to 20-hydroxyeicosatetraenoic acid (20-HETE) influences renal vascular and tubular function. To identify the cytochrome P450 (CYP) isoforms catalyzing this reaction in the mouse kidney, we analyzed the substrate specificity of Cyp4a10, 4a12a, 4a12b, and 4a14 and determined sex and strain-specific expressions. All recombinant enzymes showed high lauric acid hydroxylase activities. Cyp4a12a and Cyp4a12b efficiently hydroxylated AA to 20-HETE with V max values of about 10 nmol/nmol/min and K m values of 20 to 40 microM. 20-Carboxyeicosatetraenoic acid occurred as a secondary metabolite. AA hydroxylase activities were about 25-75-fold lower with Cyp4a10 and not detectable with Cyp4a14. Cyp4a12a and Cyp4a12b efficiently converted also eicosapentaenoic acid (EPA) to 19/20-OH- and 17,18-epoxy-EPA. In male mice, renal microsomal AA hydroxylase activities ranged between about 100 (NMRI), 45-55 (FVB/N, 129 Sv/J, BALB/c), and 25 pmol/min/mg (C57BL/6). The activities correlated with differences in Cyp4a12a protein and mRNA levels. Treatment with 5alpha-dihydrotestosterone induced both 20-HETE production and Cyp4a12a expression more than 4-fold in male C57BL/6. All female mice showed low AA hydroxylase activities (15 to 25 pmol/min/mg) and very low Cyp4a12a mRNA and protein levels, but high Cyp4a10 and Cyp4a14 expression. Renal Cyp4a12b mRNA expression was almost undetectable in both sexes of all strains. Thus, Cyp4a12a is the predominant 20-HETE synthase in the mouse kidney. Cyp4a12a expression determines the sex and strain-specific differences in 20-HETE generation and may explain sex and strain differences in the susceptibility to hypertension and target organ damage.
Keywords:Cytochrome P450, Arachidonic acid, Eicosapentaenoic acid, Mouse, Gender, Kidney, Animals, Mice
Source:Biochemical Journal
ISSN:0264-6021
Publisher:Portland Press (U.K.)
Volume:403
Number:1
Page Range:109-118
Date:April 2007
Official Publication:https://doi.org/10.1042/BJ20061328
PubMed:View item in PubMed

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