title: 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.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gross
authors.forename: Michael P
authors.initials: MP
authors.lastname: Endsley
authors.forename: Jeannine M
authors.initials: JM
authors.lastname: Moore
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Isbell
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004285:Dogs; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000097:blood / Q000633:toxicity; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D008825:Miconazole / Q000494:pharmacology / Q000627:therapeutic use*; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D000577:Amides; D001095:Arachidonic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D013450:Sulfones; C053873:11,12-dihydroxyeicosatetraenoic acid; C047008:17-octadecynoic acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; C117975:DDMS; D006899:Mixed Function Oxygenases; C409986:cytochrome P-450 omega-hydroxylase; D015126:8,11,14-Eicosatrienoic Acid