Cardiovascular disease: Healing hearts
Infarct size and reperfusion injury is reduced by cytochrome P450 monooxygenase (CYP) inhibitors.
Inhibitors of cytochrome P450 monooxygenases (CYPs) reduce infarct size and reperfusion injury in two animal models of heart attack, according to a new study published in the Proceedings of the National Academy of Sciences.
Restoration of blood flow to oxygen-deprived tissues is a priority following myocardial infarction. But this 'reperfusion' further damages ischaemic areas by inducing the production of reactive oxygen species (ROS). Recent data indicate that CYP2C9 — a member of the CYP family that modulates vascular homeostasis by converting arachidonic acid to vasoactive eicosanoids — is involved in the generation of ROS in human coronary arteries. As such, researchers from The Scripps Institute aimed to elucidate the role of CYPs in myocardial infarction.
The team's strategy capitalized on the CYP-inhibitory activity of the antibiotic chloramphenicol. In one experimental model, isolated rat hearts were deprived of blood and subsequently reperfused. Pretreatment with chloramphenicol reduced the amount of superoxide ROS produced by damaged heart tissue relative to drug-free controls. Infarct size was also significantly reduced. This result was duplicated in rabbits whose coronary arteries were occluded and subsequently reperfused in the presence of chloramphenicol. The cardioprotection conferred by the drug was apparent at the physiological level as improved post-ischaemic blood pressure.
In addition to its effect on CYPs, chloramphenicol inhibits mitochondrial protein synthesis. As mitochondria can generate ROS, the authors set out to determine whether the cardioprotective effect of the drug is mediated through its action on CYPs, on mitochondria or on both. Support for the former hypothesis included a 95% decrease in CYP activity in inhibitor-treated rat hearts, and unchanged levels of mitochondria-encoded proteins and respiratory-chain activity. The CYP inhibitors cimetidine and sulphaphenazole, which do not affect mitochondrial protein synthesis, also reduced infarct size in ischaemic rat hearts, confirming that chloramphenicol acts predominantly through CYPs in this model.
Perhaps the most significant finding of the study was that both chloramphenicol and sulphaphenazole protect heart tissue when administered after — as well as before — blood flow is interrupted. This experimental paradigm more accurately reflects the clinical situation of patients presenting to hospital after suffering a heart attack. As such, these data provide hope that exploitation of the CYP-inhibitory activity of various approved agents — such as some members of the statin family of cholesterol-lowering drugs — might improve treatment outcome for the millions of people that live through this devastating experience each year.
Suzanne Farley
References
- Granville, D. J. et al. Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors. Proc. Natl Acad. Sci. USA 101, 1321–1326 (2004) | Article | PubMed |
- Gottlieb, R. A. Cytochrome P450: major player in reperfusion injury. Arch. Biochem. Biophys. 420, 262–267 (2003) | Article | PubMed |
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