Inhibition of cardiac cytochrome P450: a new approach to cardiac ischaemia and reperfusion damage

Abstract

During reperfusion, the heart undergoes damage characterised by excessive production of reactive oxygen species (ROS), which may be generated by mitochondrial protein synthesis or the activity of cardiac cytochrome P450 enzymes (CYPs). Chloramphenicol inhibits both mitochondrial protein synthesis and the activity of CYPs, and in the perfused rat model of ischaemia/reperfusion, it decreased the release of creatine kinase and infarct size. This cardioprotective effect of chloramphenicol was not associated with mitochondrial protein synthesis, implicating the inhibition of CYPs in the cardioprotection. The ROS superoxide was generated by the heart in ischaemia/reperfusion, and this generation was inhibited by chloramphenicol. Inhibitors of CYP2C9 with no effect on mitochondrial protein synthesis, such as cimetidine and sulfaphenazole, are also cardioprotective in the perfused rat heart. Inhibition of CYP2C9 is a promising approach for the treatment of myocardial infarction, and should be further developed.