Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors.

TitleReduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors.
Publication TypeJournal Article
Year of Publication2004
AuthorsGranville, DJ, Tashakkor, B, Takeuchi, C, Gustafsson, AB, Huang, C, M Sayen, R, Wentworth, P, Yeager, M, Gottlieb, RA
JournalProc Natl Acad Sci U S A
Volume101
Issue5
Pagination1321-6
Date Published2004 Feb 3
ISSN0027-8424
KeywordsAnimals, Chloramphenicol, Cimetidine, Creatine Kinase, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Enzyme Inhibitors, Mitochondria, Heart, Myocardial Ischemia, Myocardial Reperfusion Injury, Rabbits, Rats, Reactive Oxygen Species, Sulfaphenazole
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.

DOI10.1073/pnas.0308185100
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID14734800
PubMed Central IDPMC337051
Grant List5T32AI07606 / AI / NIAID NIH HHS / United States
DK 07022 / DK / NIDDK NIH HHS / United States
HL 48908 / HL / NHLBI NIH HHS / United States
HL 60590 / HL / NHLBI NIH HHS / United States
HL 61518 / HL / NHLBI NIH HHS / United States