title: Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors.
abstract: Ischemia and reperfusion both contribute to tissue damage after myocardial infarction. Although many drugs have been shown to reduce infarct size when administered before ischemia, few have been shown to be effective when administered at reperfusion. Moreover, although it is generally accepted that a burst of reactive oxygen species (ROS) occurs at the onset of reperfusion and contributes to tissue damage, the source of ROS and the mechanism of injury is unclear. We now report the finding that chloramphenicol administered at reperfusion reduced infarct size by 60% in a Langendorff isolated perfused rat heart model, and that ROS production was also substantially reduced. Chloramphenicol is an inhibitor of mitochondrial protein synthesis and is also an inhibitor of a subset of cytochrome P450 monooxygenases (CYPs). We could not detect any effect on mitochondrial encoded proteins or mitochondrial respiration in chloramphenicol-perfused hearts, and hypothesized that the effect was caused by inhibition of CYPs. We tested additional CYP inhibitors and found that cimetidine and sulfaphenazole, two CYP inhibitors that have no effect on mitochondrial protein synthesis, were also able to reduce creatine kinase release and infarct size in the Langendorff model. We also showed that chloramphenicol reduced infarct size in an open chest rabbit model of regional ischemia. Taken together, these findings implicate CYPs in myocardial ischemia/reperfusion injury.
authors.affiliation: Departments of Molecular and Experimental Medicine, Cell Biology, Chemistry, and Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
authors.forename: Babak
authors.initials: B
authors.lastname: Tashakkor
authors.forename: Cindy
authors.initials: C
authors.lastname: Takeuchi
authors.forename: Asa B
authors.initials: AB
authors.lastname: Gustafsson
authors.forename: Chengqun
authors.initials: C
authors.lastname: Huang
authors.forename: M Richard
authors.initials: MR
authors.lastname: Sayen
authors.forename: Paul
authors.initials: P
authors.lastname: Wentworth
authors.forename: Mark
authors.initials: M
authors.lastname: Yeager
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D002701:Chloramphenicol / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011817:Rabbits; D051381:Rats; D017382:Reactive Oxygen Species; D013426:Sulfaphenazole / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013426:Sulfaphenazole; D002701:Chloramphenicol; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D003402:Creatine Kinase