Proposed mechanisms of protection by EETs against selected cardiotoxic drugs
The listed compounds are known substrates for CYP2J2.
| CYP2J2 Substrate | FDA Approval Package Cardiac Warnings | Mechanism Contributing to Cardiotoxicity | Circumstantial Evidence for Mitigation of Cardiotoxicity by EETs |
|---|---|---|---|
| Cyclosporine A (Tang et al., 2011) | Hypertension, tachycardia, myocardial infarction | Oxidative stress and/or mitochondrial dysfunction | In a CYP2J2 transgenic mouse, heart failure-induced oxidative stress was mitigated by EETs; EETs increased expression of antioxidant enzymes and reduced ROS levels (Wang et al., 2014; Akhnokh et al., 2016). |
| DOX (Zhang et al., 2009b) | ECG abnormalities, tachyarrhythmias, reduction in LVEF and congestive heart failure | In a CYP2J2 transgenic mouse, DOX-induced ROS levels were reduced compared with wild-type. CYP2J2 tr mice had preserved mitochondrial structure and membrane potential (Zhang et al., 2009b) | |
| Sunitinib (Aparicio-Gallego et al., 2011) | Decreased LVEF and heart failure, QT interval prolongation and TdP, cardiomyopathy. | In sEH null mice, increased circulating EETs limited mitochondrial damage following ischemia (Akhnokh et al., 2016) | |
| Amiodarone (Isomoto et al., 2006) | Ventricular fibrillation, ventricular tachycardia, QTc prolongation. | Activation of apoptotic pathways and caspases | EETs inhibited pro-apoptotic pathways through increasing activity of the pro-survival enzyme phosphoinositide 3 kinase (PI3K) in mouse primary cardiomyocytes (Dhanasekaran et al., 2008) |
| Sunitinib (Aparicio-Gallego et al., 2011) | As above | ||
| Astemizole (Minotti, 2010) | QTc interval prolongation in a dose related manner. Cardiac dysrhythmia | Changes in electrophysiology | No evidence to date |
| Terfenadine (Minotti, 2010) | |||
| Thioridazine (Menkes and Knight, 2002; Minotti, 2010) | |||
| Sunitinib (Aparicio-Gallego et al., 2011) | As above. | Cardiac hypertrophy | In an animal model of isoproterenol-induced cardiac hypertrophy, use of sEH inhibitors protected in rats (Althurwi et al., 2013). |
| 5-Fluorouracil (Alter et al., 2006) | Angina, myocardial infarction, arrhythmia, and heart failure | Vasoconstriction | 11,12-EET caused relaxation of rat coronary arteries and renal and cerebral arteries of rats and rabbits. (Campbell et al., 1996; Fisslthaler et al., 1999; Imig et al., 2001; Larsen et al., 2006; Dimitropoulou et al., 2007) |
| Cyclosporine A (Rezzani et al., 2005) | As above | Increase in intracellular calcium concentration through the calcium sensing receptor (CaSR) | No evidence to date |
| Eperisone (Saegusa et al., 1991; Yamagiwa et al., 2014) | QTc interval prolongation | Inhibition of nicotinic and muscarinic receptors | No evidence to date |
ECG, electrocardiography; EET, epoxyeicosatrienoic acid; LVEF, left ventricular ejection fraction; ROS, reactive oxygen species; TdP, torsades de pointes.