Role of cytochrome P450 enzymes in the pathogenesis of cardiac hypertrophy and doxorubicin-induced cardiotoxicity.

摘要

Heart failure (HF) affects more than 5 million patients in North America with about half a million new cases every year. Cardiac hypertrophy and drug-induced cardiotoxicity are two important predisposing factors to HF. Several cytochrome P450 (CYP) enzymes have been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy and HF. Moreover, CYP enzymes have been shown to metabolize arachidonic acid to the cardioprotective epoxyeicosatrienoic acids (EETs) and the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE). Therefore, the objective of the present work was to investigate the role of CYP enzymes and CYP-mediated arachidonic acid metabolism in the pathogenesis of cardiac hypertrophy and doxorubicin (DOX)-induced cardiotoxicity. Our results showed that isoproterenol-induced cardiac hypertrophy caused a significant induction of CYP1A1, CYP1B1, and CYP4A3 and a significant inhibition of CYP2C11 and CYP2E1 gene expression in the rat heart. In addition, there was a significant induction of the soluble epoxide hydrolase (sEH) which metabolizes the EETs to the less biologically active dihydroxyeicosatrienoic acids. These changes in CYP and sEH expression altered CYP-mediated arachidonic acid metabolism with a decrease in the EETs and an increase in the 20-HETE formation rates. Interestingly, we have also shown that induction of CYPIA1 and CYP1BI by aryl hydrocarbon receptor ligands caused hypertrophy of the cardiac derived H9c2 cells. With regard to DOX-induced cardiotoxicity, we demonstrated that DOX induces several CYP and sEH enzymes in both the rat heart and the H9c2 cells. The overall alteration of CYP and sEH expression resulted in altered CYP-mediated arachidonic acid metabolism with a significant increase in the 20-HETE and a significant decrease of the EETs formation. Interestingly, we have demonstrated that acute DOX toxicity alters the expression of CYP and sEH in an organ-specific manner. Most notably, sEH induction and the subsequent decrease in formation of EETs were observed only in the heart of DOX-treated rats but not in the kidney or the liver. In conclusion, induction of cardiac CYP and sEH enzymes and the subsequent derailed CYP-mediated arachidonic acid metabolism may be involved in the pathogenesis of cardiac hypertrophy and DOX-induced cardiotoxicity and their progression to HF.