title: Inhibition and inactivation of human CYP2J2: Implications in cardiac pathophysiology and opportunities in cancer therapy.
abstract: Extrahepatic cytochrome P450 enzymes (CYP450) are pivotal in the metabolism of endogenous substrates and xenobiotics. CYP2J2 is a major cardiac CYP450 and primarily metabolizes polyunsaturated fatty acids such as arachidonic acid to cardioactive epoxyeicosatrienoic acids. Due to its role in endobiotic metabolism, CYP2J2 has been actively studied in recent years with the focus on its biological functions in cardiac pathophysiology. Additionally, CYP2J2 metabolizes a number of xenobiotics such as astemizole and terfenadine and is potently inhibited by danazol and telmisartan. Notably, CYP2J2 is found to be upregulated in multiple cancers. Hence a number of specific CYP2J2 inhibitors have been developed and their efficacy in inhibiting tumor progression has been actively studied. CYP2J2 inhibitor such as C26 (1-[4-(vinyl)phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) caused marked reduction in tumor proliferation and migration as well as promoted apoptosis in cancer cells. In this review, we discuss the role of CYP2J2 in cardiac pathophysiology and cancer therapeutics. Additionally, we provide an update on the substrates, reversible inhibitors and irreversible inhibitors of CYP2J2. Finally, we discuss the current gaps and future directions in CYP2J2 research.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: Aneesh
authors.initials: A
authors.lastname: Karkhanis
authors.affiliation: Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, OEW901, Ho Sin Han Campus, The Hong Kong Baptist University, 224 Waterloo Road, Kowloon, Hong Kong, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543; Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609. Electronic address: eric.chan@nus.edu.sg.
authors.forename: Eric Chun Yong
authors.initials: ECY
authors.lastname: Chan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000201:enzymology* / Q000503:physiopathology; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D013379:Substrate Specificity; D015262:Xenobiotics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2
keywords: Arachidonic acid; CYP2J2; Cardiology; Enzyme inhibition; Epoxyeicosatrienoic acids; Oncology