Abstract
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
Highlights
Drug-induced cardiotoxicity affects all components and functions of the cardiovascular system
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)–derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2)
P450 enzymes belonging to the CYP4A and 4F subfamily produce 20-hydroxyeicosatetrenoic acid (20-HETE) from AA (Miyata et al, 2005; Harmon et al, 2006; Tang et al, 2010) and show increased expression in cardiovascular disease. 20-HETE has antagonistic effects toward EETs, exacerbating disease processes (Jenkins et al, 2009)
Summary
Drug-induced cardiotoxicity affects all components and functions of the cardiovascular system. Investigation of the CYP2J2 epoxidation pathway in various tissues has provided evidence to support the idea that CYP2J2, and EETs, have a biologically protective role, and this is emphasized by the growing potential of sEH inhibitors Investigation of these small-molecule inhibitors suggests a link between sEH inhibition and improved cardiovascular health and, given the high expression of CYP2J2 in the human heart, suggest a possible protective role for CYP2J2 in drug-induced cardiotoxicity. Rat cardiac cell lines, such as rat myoblast H9c2 cells, have been used to investigate cardiac biology and toxicology; they lack key functional features of cardiomyocytes, exhibit a mainly skeletal muscle phenotype, and do not respond to electrical stimulation (Kimes and Brandt, 1976); they have recently been used to investigate the cardioprotective effects of drugs after oxidative damage (Zhou et al, 2016), suggesting the potential use of these cells in investigating the mechanisms of cardioprotection from druginduced cardiotoxicity In both dogs and monkeys, a single CYP2J isoform (CYP2J2) has been identified (Nelson, 2009). Rat CYP2J3 has high levels of protein and mouse CYP2J11 has high RNA expression in the heart, indicating that there are often discrepancies between RNA and protein expression in different homologs
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