Faculty Collaboration Database

Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway. Circ Res 2004 Oct 15;95(8):e65-71

Date

09/25/2004

Pubmed ID

15388642

DOI

10.1161/01.RES.0000146277.62128.6f

Scopus ID

2-s2.0-9644278449 (requires institutional sign-in at Scopus site)   95 Citations

Abstract

Cytochrome P450s (CYP) and their arachidonic acid (AA) metabolites have important roles in regulating vascular tone, but their function and specific pathways involved in modulating myocardial ischemia-reperfusion injury have not been clearly established. Thus, we characterized the effects of several selective CYPomega-hydroxylase inhibitors and a CYPomega-hydroxylase metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), on the extent of ischemia-reperfusion injury in canine hearts. During 60 minutes of ischemia and particularly after 3 hours of reperfusion, 20-HETE was produced at high concentrations. A nonspecific CYP inhibitor, miconazole, and 2 specific CYPomega-hydroxylase inhibitors, 17-octadecanoic acid (17-ODYA) and N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly inhibited 20-HETE production during ischemia-reperfusion and produced a profound reduction in myocardial infarct size (expressed as a percent of the area at risk) (19.6+/-1.7% [control], 8.4+/-2.5% [0.96 mg/kg miconazole], 5.9+/-2.2% [0.28 mg/kg 17-ODYA], and 10.8+/-1.8% [0.40 mg/kg DDMS], P<0.05, respectively). Conversely, exogenous 20-HETE administration significantly increased infarct size (26.9+/-1.9%, P<0.05). Several CYPomega-hydroxylase isoforms, which are known to produce 20-HETE such as CYP4A1, CYP4A2, and CYP4F, were demonstrated to be present in canine heart tissue and their activity was markedly inhibited by incubation with 17-ODYA. These results indicate an important endogenous role for CYPomega-hydroxylases and in particular their product, 20-HETE, in exacerbating myocardial injury in canine myocardium. The full text of this article is available online at http://circres.ahajournals.org.

Author List

Nithipatikom K, Gross ER, Endsley MP, Moore JM, Isbell MA, Falck JR, Campbell WB, Gross GJ

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Amides
Animals
Arachidonic Acids
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System
Dogs
Fatty Acids, Unsaturated
Female
Hydroxyeicosatetraenoic Acids
Isoenzymes
Male
Miconazole
Microsomes
Mixed Function Oxygenases
Myocardial Infarction
Myocardial Ischemia
Myocardial Reperfusion Injury
Myocardium
Sulfones