Cytochrome P450 enzymes (P450) consist of a family of membrane-bound hemeproteins that are mainly expressed in the human liver and conventionally associated with endobiotic and xenobiotic metabolism (Michaels & Wang, 2014; Nebert & Russell, 2002; Paine et al., 2006). Notably, CYP3A is the most abundant hepatic P450 (approximately 28.8% of total hepatic P450) (Michaels & Wang, 2014) and estimated to metabolize >50% of clinically-used drugs. In contrast to xenobiotic metabolism, relatively fewer studies have delved into the investigation of the physiological roles of P450 despite early evidence since the 1970s regarding their endogenous functions (Nebert, 1991). Majority of the CYP1, CYP2 and CYP4 isoforms are involved in the biotransformation of arachidonic acid (AA), an omega-6 polyunsaturated fatty acid (PUFA), to eicosanoid metabolites including epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) which possess a myriad of biological activities including effects on vascular tone and ion channel activity (Campbell & Falck, 2007; Fer et al., 2008; Meves, 2008; Miyata & Roman, 2005; Rifkind, Lee, Chang, & Waxman, 1995; S. Wu, Moomaw, Tomer, Falck, & Zeldin, 1996; Zeldin, DuBois, Falck, & Capdevila, 1995). However, the pathophysiological implications of P450 in AA metabolism are comparatively less established compared to the body of research characterizing the cyclooxygenase (COX)- and lipoxygenase (LOX)-mediated metabolism of AA to prostanoids and leukotrienes respectively, which are implicated in anti- and pro-inflammatory conditions as reviewed extensively (Yamaguchi, Botta, & Holinstat, 2022). Examples of other physiologically important endogenous substrates and metabolites with biological functions mediated by P450 include cholesterol, bile acids, steroid hormones, vitamin D and retinoic acid (Nebert, Wikvall, & Miller, 2013). This underpins the wide-ranging implications of P450 in both physiology and pathophysiology whereby diseases could develop due to intrinsic (e.g. genetic polymorphism) and/or extrinsic (e.g. drug-drug interaction (DDI)) perturbations of P450-mediated metabolism of endogenous substrates.

Emergent studies have focused increasingly on the roles of extrahepatic P450 in both physiology and pathophysiology. In particular, CYP2J2 is an epoxygenase that is predominantly expressed in cardiac tissues (S. Wu et al., 1996). Its role in AA metabolism hints at implications in the regulation of cardiac electrophysiology due to the ion channel activities associated with its biologically-active EET metabolites (J. Chen, Capdevila, Zeldin, & Rosenberg, 1999; H. C. Lee et al., 1999; Lu, Hoshi, Weintraub, Spector, & Lee, 2001; Y.-F. Xiao et al., 2004; Y. F. Xiao, Huang, & Morgan, 1998; Y. F. Xiao, 2007). Concurrently, the upregulation of CYP2J2 in several solid tumours promotes resistance to chemotherapeutic drugs that are substrates of CYP2J2 but also poses an opportunity for therapeutic interventions in oncology drug development (El-Serafi, Oerther, Zhao, & Hassan, 2022; Evangelista, Cho, Aliwarga, & Totah, 2020; Karkhanis, Hong, & Chan, 2017; Narjoz et al., 2014; X. Zou & Mo, 2021). Some extrahepatic P450 have additionally been implicated in tissue-specific biotransformation of xenobiotics resulting in targeted toxicities (X. Ding & Kaminsky, 2003). An example is CYP2A13 which is predominantly expressed in lung and respiratory tract tissues and plays a significant role in toxicant-induced pulmonary lesions and lung cancer as it participates in the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a key component of cigarette smoke and an established lung procarcinogen (Vrzal, Moorthy, & Ghose, 2021). There is indeed an impetus to investigate and characterize the roles of extrahepatic P450 in our human body.

Taken together, growing evidence points to the crucial roles of extrahepatic P450 in both human physiology and pathophysiology. In this review, we discuss CYP2J2-mediated metabolism of AA in the heart with a focus on the in vitro and in vivo implications of its enzyme kinetics as well as inhibition and inactivation of its activity by xenobiotics. The role of CYP2J2-mediated metabolism of AA to EETs in cardiac electrophysiology is also expounded.