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Investigating the association between CYP2J2 inhibitors and QT prolongation: a literature review
Alexandra M Wiley1, Jade Yang1, Rivcka Madhani1
1Department of Medicinal Chemistry, University of WA School of Pharmacy, Seattle, WA, USA.
Abstract:
Drug withdrawal post-marketing due to cardiotoxicity is a major concern for drug developers, regulatory agencies, and patients. One common mechanism of cardiotoxicity is through inhibition of cardiac ion channels, leading to prolongation of the QT interval and sometimes fatal arrythmias. Recently, oxylipin signaling compounds have been shown to bind to and alter ion channel function, and disruption in their cardiac levels may contribute to QT prolongation. Cytochrome P450 2J2 (CYP2J2) is the predominant CYP isoform expressed in cardiomyocytes, where it oxidizes arachidonic acid to cardioprotective epoxyeicosatrienoic acids (EETs). In addition to roles in vasodilation and angiogenesis, EETs bind to and activate various ion channels. CYP2J2 inhibition can lower EET levels and decrease their ability to preserve cardiac rhythm. In this review, we investigated the ability of known CYP inhibitors to cause QT prolongation using Certara's Drug Interaction Database. We discovered that among the multiple CYP isozymes, CYP2J2 inhibitors were more likely to also be 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 to interact with QT-prolonging drugs. The four residues are located near the opening of egress channel 2, highlighting the potential importance of this channel in CYP2J2 binding and inhibition. These findings suggest that if a drug inhibits CYP2J2 and interacts with one of these four residues, then it may have a higher risk of QT prolongation and more preclinical studies are warranted to assess cardiovascular safety.
Insights
Drug developers should screen for cardiotoxicity risk. Inhibitors of Cytochrome P450 2J2 (CYP2J2) are twice as likely to cause QT prolongation, a dangerous heart rhythm issue.
Area of Science:
- Cardiovascular Pharmacology
- Drug Metabolism
- Molecular Toxicology
Background:
- Drug-induced cardiotoxicity, particularly QT prolongation leading to fatal arrhythmias, is a significant post-marketing concern.
- Oxylipins, including epoxyeicosatrienoic acids (EETs), are crucial for maintaining cardiac rhythm by interacting with ion channels.
- Cytochrome P450 2J2 (CYP2J2) is the primary enzyme in cardiomyocytes responsible for producing cardioprotective EETs from arachidonic acid.
Purpose of the Study:
- To investigate the association between Cytochrome P450 (CYP) enzyme inhibition and QT prolongation.
- To identify specific CYP isoforms and drug interactions that increase the risk of cardiotoxicity.
- To explore the molecular mechanisms underlying CYP-mediated cardiotoxicity, focusing on CYP2J2.
Main Methods:
- Analysis of the Certara's Drug Interaction Database to correlate CYP inhibitors with QT-prolonging drugs.
- Utilizing molecular docking simulations to predict binding interactions between CYP2J2 and QT-prolonging drug candidates.
- Identifying key amino acid residues within CYP2J2 involved in drug binding and inhibition.
Main Results:
- CYP2J2 inhibitors demonstrated a significantly higher likelihood (approximately 2-fold) of being associated with QT-prolonging drugs compared to other CYP isoforms.
- Molecular docking identified four critical amino acid residues (Phe61, Ala223, Asn231, Leu402) in CYP2J2 that interact with QT-prolonging inhibitors.
- These residues are located near egress channel 2, suggesting its importance in CYP2J2 inhibition and subsequent cardiotoxicity.
Conclusions:
- Inhibition of CYP2J2 is strongly linked to QT prolongation, highlighting its role in drug-induced cardiotoxicity.
- Drugs inhibiting CYP2J2 and interacting with the identified amino acid residues may pose a higher cardiovascular safety risk.
- Further preclinical evaluation of cardiovascular safety is warranted for drugs targeting CYP2J2, especially those interacting with key binding sites.
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