Cytochrome P450-dependent renal arachidonic acid metabolism in desoxycorticosterone acetate-salt hypertensive mice.
Cytochrome P450 (P450)-dependent arachidonic acid metabolites may act as mediators in the regulation of vascular tone and renal function. We studied arachidonic acid hydroxylase activities in renal microsomes from normotensive NMRI mice, desoxycorticosterone acetate (DOCA)-salt hypertensive mice, and DOCA-salt mice treated with either lovastatin or bezafibrate, both of which improve hemodynamics in this model. Control renal microsomes had arachidonic acid hydroxylase activities of 175+/-12 pmol. min(-1). mg(-1). The metabolites formed were 20- and 19-hydroxyarachidonic acid, representing approximately 80% and approximately 20% of the total hydroxylation. Treatment with DOCA-salt resulted in significantly decreased hydroxylase activities (to 84+/-4 pmol. min(-1). mg(-1)) of the total microsomal P450 content and a decrease in immunodetectable Cyp4a proteins. Lovastatin had no effect on these variables, whereas bezafibrate increased arachidonic acid hydroxylase activities to 163+/-12 pmol. min(-1). mg(-1). In situ hybridization with probes for Cyp4a-10, 12, and 14 revealed that Cyp4a-14 was the P450 isoform most strongly induced by bezafibrate. The expression was concentrated in the cortical medullary junction and was localized predominantly in the proximal tubules. In conclusion, these results suggest that the capacity to produce 20-hydroxyarachidonic acid is impaired in the kidneys of DOCA-salt hypertensive mice. Furthermore, bezafibrate may ameliorate hemodynamics in this model by restoring P450-dependent arachidonic acid hydroxylase activities. Lovastatin, on the other hand, exerts its effects via P450-independent mechanisms.
Honeck
H
H
Max Delbrück Center for Molecular Medicine and Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
Gross
V
V
Erdmann
B
B
Kärgel
E
E
Neunaber
R
R
Milia
A F
AF
Schneider
W
W
Luft
F C
FC
Schunck
W H
WH
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001629:Bezafibrate / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003900:Desoxycorticosterone; D006893:Hydroxyeicosatetraenoic Acids / Q000032:analysis; D006900:Hydroxylation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D017403:In Situ Hybridization; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009392:Nephrectomy; D012333:RNA, Messenger / Q000378:metabolism; D012965:Sodium Chloride
D006893:Hydroxyeicosatetraenoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D016718:Arachidonic Acid; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D009249:NADP; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D001629:Bezafibrate