title: Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism.
abstract: Metabolism of arachidonic acid by cytochrome P450 (CYP) to biologically active eicosanoids has been recognized increasingly as an integral mediator in the pathogenesis of cardiovascular and metabolic disease. CYP epoxygenase-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET + DHET) and CYP ω-hydroxylase-derived 20-hydroxyeicosatetraenoic acid (20-HETE) exhibit divergent effects in the regulation of vascular tone and inflammation; thus, alterations in the functional balance between these parallel pathways in liver and kidney may contribute to the pathogenesis and progression of metabolic syndrome. However, the impact of metabolic dysfunction on CYP-mediated formation of endogenous eicosanoids has not been well characterized. Therefore, we evaluated CYP epoxygenase (EET + DHET) and ω-hydroxylase (20-HETE) metabolic activity in liver and kidney in apoE(-/-) and wild-type mice fed a high-fat diet, which promoted weight gain and increased plasma insulin levels significantly. Hepatic CYP epoxygenase metabolic activity was significantly suppressed, whereas renal CYP ω-hydroxylase metabolic activity was induced significantly in high-fat diet-fed mice regardless of genotype, resulting in a significantly higher 20-HETE/EET + DHET formation rate ratio in both tissues. Treatment with enalapril, but not metformin or losartan, reversed the suppression of hepatic CYP epoxygenase metabolic activity and induction of renal CYP ω-hydroxylase metabolic activity, thereby restoring the functional balance between the pathways. Collectively, these findings suggest that the kinin-kallikrein system and angiotensin II type 2 receptor are key regulators of hepatic and renal CYP-mediated eicosanoid metabolism in the presence of metabolic syndrome. Future studies delineating the underlying mechanisms and evaluating the therapeutic potential of modulating CYP-derived EETs and 20-HETE in metabolic diseases are warranted.
authors.affiliation: Div. of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Univ. of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Theken
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Deng
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.forename: Akinyemi
authors.initials: A
authors.lastname: Oni-Orisan
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Miller
authors.forename: M Alison
authors.initials: MA
authors.lastname: Kannon
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015777:Eicosanoids / Q000378:metabolism*; D004656:Enalapril / Q000627:therapeutic use*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006937:Hypercholesterolemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012084:Renin-Angiotensin System / Q000187:drug effects; D012720:Severity of Illness Index
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D015777:Eicosanoids; D012333:RNA, Messenger; D004656:Enalapril; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; C409986:cytochrome P-450 omega-hydroxylase