Granville David J, Tashakkor Babak, Takeuchi Cindy, Gustafsson Asa B, Huang Chengqun, Sayen M Richard, Wentworth Paul, Yeager Mark, Gottlieb Roberta A
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.
Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1321-6. doi: 10.1073/pnas.0308185100. Epub 2004 Jan 20.
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.
缺血和再灌注均会导致心肌梗死后的组织损伤。尽管许多药物在缺血前给药时已显示可减小梗死面积，但很少有药物在再灌注时给药被证明是有效的。此外，尽管人们普遍认为在再灌注开始时会出现活性氧（ROS）爆发并导致组织损伤，但ROS的来源和损伤机制尚不清楚。我们现在报告一项发现，即在Langendorff离体灌注大鼠心脏模型中，再灌注时给予氯霉素可使梗死面积减小60%，并且ROS生成也显著减少。氯霉素是线粒体蛋白质合成的抑制剂，也是细胞色素P450单加氧酶（CYPs）的一个亚组的抑制剂。我们在氯霉素灌注的心脏中未检测到对线粒体编码蛋白或线粒体呼吸的任何影响，并推测该作用是由CYPs的抑制引起的。我们测试了其他CYP抑制剂，发现西咪替丁和磺胺苯吡唑这两种对线粒体蛋白质合成无影响的CYP抑制剂，在Langendorff模型中也能够减少肌酸激酶释放和梗死面积。我们还表明，氯霉素在开放胸腔兔局部缺血模型中减小了梗死面积。综上所述，这些发现表明CYPs与心肌缺血/再灌注损伤有关。
