Investigating the Association between CYP2J2 Inhibitors and QT Prolongation: A Literature Review.

Drug withdrawal post-marketing due tocardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity isthroughinhibition of cardiac ion channels, leading to prolongation of the QT intervaland sometimes fatal arrythmias. Recently, oxylipinsignaling compounds have been shown to bind toand alter ion channel function,and disruption in their cardiac levels may contribute to QTprolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes,where it oxidizes arachidonic acid to cardioprotectiveepoxyeicosatrienoic acids (EETs).In addition to roles in vasodilation and angiogenesis, EETs bind to and activate various ion channels. CYP2J2inhibitioncan lower EET levelsand decrease their ability to preserve cardiac rhythm. In this review, we investigatedthe ability of knownCYPinhibitorsto cause QT prolongation using Certara's Drug Interaction Database. We discovered thatamong the multipleCYP isozymes, CYP2J2 inhibitors were more likelyto alsobe QT-prolonging drugs (by approximately 2-fold). We explored potential binding interactions between these inhibitors and CYP2J2 using molecular docking and identified four amino acid residues(Phe61, Ala223, Asn231, and Leu402)predicted tointeract with QT-prolonging drugs. The four residues are located near the opening of egress channel 2, highlighting the potential importance of this channelin CYP2J2 binding and inhibition. These findings suggest that if a drug inhibits CYP2J2 and interacts with one of these four residues,then it mayhave a higher risk ofQTprolongation and more preclinical studies are warranted to assess cardiovascular safety.