Cytochrome P450 2J2: Potential Role In Drug Metabolism And Cardiotoxicity

Drug-induced cardiotoxicity may be modulated by protective endogenous arachidonic acid (AA) derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesised by cytochrome P450 2J2 (CYP2J2). In addition, CYP2J2 metabolises both exogenous and endogenous substrates and is involved in phase I metabolism of a variety of structurally diverse compounds. This project addresses the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and metabolism of drugs. An in vitro model was established in human cardiac myocytes and EA.hy926 cells which was shown to be good predictor of astemizole drug toxicity. sEH inhibitor t-AUCB and exogenous EETs protected cells from toxicity and CYP2J2 inhibitor, MSPPOH and the PLA2 inhibitors quinacrine dihydrochloride and LY311727 also showed a preservation of or an increase in ATP in toxicity compared to cells treated with astemizole alone. Expression of CYP2J2 and sEH was present in both cell types with higher expression in HCM. Astemizole increased CYP2J2 and decreased sEH gene expression. MSSPOH or t-AUCB in conjunction with astemizole modulated gene and protein expression of both enzymes. Investigation of astemizole metabolism by CYP2J2 showed concentration dependent metabolism to its o-demethylated product which was inhibited by endogenous CYP2J2 substrate AA in a recombinant bactosome system. Further study into the mechanism of astemizole toxicity showed a concentration dependent increase in exosomes compared to the non-toxic drug loratadine. This data suggests that CYP2J2 may protect in in vitro drug induced toxicity and changes in the expression or activity of this enzyme may alter drug and EET concentrations leading to modulation of drug induced toxicity. Understanding more widely the role and possible protection by CYP2J2 in the heart is worthy of further study.