Inhibition of cytochrome P450omega-hydroxylase: a novel endogenous cardioprotective pathway.

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.

• Authors: Kasem Nithipatikom, Eric R Gross, Michael P Endsley, Jeannine M Moore, Marilyn A Isbell, John R Falck, William B Campbell, Garrett J Gross
• Journal: Circulation research (Circ Res) Vol. 95 Issue 8 Pg. e65-71 (Oct 15 2004) ISSN: 1524-4571 [Electronic] United States
• PMID: 15388642 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 14,15-dihydroxyeicosatrienoic acid
• Amides
• Arachidonic Acids
• Cytochrome P-450 Enzyme Inhibitors
• Fatty Acids, Unsaturated
• Hydroxyeicosatetraenoic Acids
• Isoenzymes
• Sulfones
• 11,12-dihydroxyeicosatetraenoic acid
• 17-octadecynoic acid
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Miconazole
• Cytochrome P-450 Enzyme System
• DDMS
• Mixed Function Oxygenases
• cytochrome P-450 omega-hydroxylase
• 8,11,14-Eicosatrienoic Acid

Topics

• 8,11,14-Eicosatrienoic Acid (analogs & derivatives)
• Amides (pharmacology, therapeutic use)
• Animals
• Arachidonic Acids (metabolism)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (physiology)
• Dogs
• Fatty Acids, Unsaturated (pharmacology, therapeutic use)
• Female
• Hydroxyeicosatetraenoic Acids (biosynthesis, blood, toxicity)
• Isoenzymes (antagonists & inhibitors, physiology)
• Male
• Miconazole (pharmacology, therapeutic use)
• Microsomes (enzymology)
• Mixed Function Oxygenases (antagonists & inhibitors, physiology)
• Myocardial Infarction (enzymology, pathology)
• Myocardial Ischemia (enzymology, pathology, prevention & control)
• Myocardial Reperfusion Injury (enzymology, pathology, prevention & control)
• Myocardium (enzymology)
• Sulfones (pharmacology, therapeutic use)