TY - JOUR
T1 - Inhibition and inactivation of human CYP2J2
T2 - Implications in cardiac pathophysiology and opportunities in cancer therapy
AU - Karkhanis, Aneesh
AU - Hong, Yanjun
AU - Chan, Eric Chun Yong
N1 - This work was supported by the Singapore Ministry of Education Tier 1 Academic Research Funding [Grant R-148-000-204-112] provided to Eric Chun Yong Chan.
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
KW - Arachidonic acid
KW - Cardiology
KW - CYP2J2
KW - Enzyme inhibition
KW - Epoxyeicosatrienoic acids
KW - Oncology
UR - http://www.scopus.com/inward/record.url?scp=85015684145&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2017.02.017
DO - 10.1016/j.bcp.2017.02.017
M3 - Review article
C2 - 28237650
AN - SCOPUS:85015684145
SN - 0006-2952
VL - 135
SP - 12
EP - 21
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
ER -
