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(Circulation Research. 2004;95:e65.)
© 2004 American Heart Association, Inc.

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Inhibition of Cytochrome P450-Hydroxylase

A Novel Endogenous Cardioprotective Pathway

Kasem Nithipatikom, Eric R. Gross, Michael P. Endsley, Jeannine M. Moore, Marilyn A. Isbell, John R. Falck, William B. Campbell, Garrett J. Gross

From the Department of Pharmacology and Toxicology (K.N., E.R.G., M.P.E., J.M.M., M.A.I., W.B.C., G.J.G.), Medical College of Wisconsin, Milwaukee; and the Departments of Biochemistry and Pharmacology (J.R.F.), University of Texas Southwestern Medical Center, Dallas.

Correspondence to Garrett J. Gross, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ggross{at}mcw.edu

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 CYP-hydroxylase inhibitors and a CYP-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 CYP-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 CYP-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 CYP-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.

Key Words: arachidonic acid metabolites • cytochrome p450 • 20-HETE • ischemia • reperfusion

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