Cytochrome P450 2J2 (CYP2J2) is aprotein that in humans is encoded by theCYP2J2gene.[4][5] CYP2J2 is a member of the cytochrome P450 superfamily ofenzymes. The enzymes areoxygenases which catalyze many reactions involved in the metabolism of drugs and otherxenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.
The F-G loop mediates the binding and passage of substrates, and its hydrophobic region containing residues Trp-235, Phe-239 and Ille-236 allows theenzyme to interact with cellular membranes. Mutations to hydrophilic residues in the F-G loop alter the binding mechanism by changing insertion depth of theenzyme into the membrane.
CYP2J2 is expressed predominately in the heart and, to a lesser extent, in other tissues such as the liver, gastrointestinal tract, pancreas, lung, andcentral nervous system.[7]
CYP2J2 localizes to theendoplasmic reticulum and is thought to be a prominent enzyme responsible for metabolizing endogenouspolyunsaturated fatty acids to signaling molecules.[8] It metabolizesarachidonic acid to the following eicosatrienoic acidepoxides (termed EETs): 5,6-epoxy-8Z,11Z,14Z-EET, 8,9-epoxy-8Z,11Z,14Z-EET, 11,12-epoxy-5Z,8Z,14Z-EET, and 14,15-epoxy-5Z,8Z,11Z-EET. CYP2J2 also metabolizeslinoleic acid to 9,10-epoxy octadecenoic acids (also termedvernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termedcoronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin);docosahexaenoic acid to variousepoxydocosapentaenoic acids (also termed EDPs); andeicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[9]
CYP2J2, along withCYP219,CYP2C8,CYP2C9, and possiblyCYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.[10][11]
Animal model studies implicate the EETs, EDPs, and EEQs in regulatinghypertension, the development ofmyocardial infarction and other damage to the heart, the growth of various cancers,inflammation, blood vessel formation, and pain perception; limited studies suggest but have not proven that these epoxides may function similarly in humans (seeepoxyeicosatrienoic acid,epoxydocosapentaenoic acid, andepoxygenase pages).[11] Vernolic and coronaric acids are potentially toxic, causing multiple organ failure and respiratory distress when injected into animals.[11]
Tissue samples containing carcinomas were obtained from 130 subjects and analyzed for expression of CYP2J2. Increased detection of CYP2J2 mRNA and protein were evident in 77% of patient carcinoma cell lines. Cell proliferation was positively regulated by CYP2J2 and furthermore CYP2J2 was shown to promote tumor progression.[12] There was also a greater amount of CYP2J2 mRNA in various tumor types, including esophagealadenocarcinoma,breast carcinoma, andstomach carcinoma compared to that of surrounding normal tissue.
The overexpression of CYP2J2 and its effects on carcinoma cells are also evident when EETs are administered exogenously, suggesting a link between the production of EETs and cancer progression. Furthermore, tumor progression increases at a faster rate in cell lines with over-expression of CYP2J2 compared to control cancer cell lines.[12]
CYP2J2 is over-expressed in a number of cancers, and forced over-expression of CYP2J2 in human cancer cells lines accelerates proliferation and protects cells againstapoptosis.[7]
HETEs and EETs derived from CYP2J2 have also been shown to contribute to the proper functioning of the cardiovascular system and the regulation of the renal and pulmonary systems in humans.[citation needed] CYP2J2 is readily expressed in thecardiac myocytes andendothelial cells of the coronary artery where various EETs are produced. The presence of EETs relaxes vascular smooth muscle cells by hyperpolarizing the cell membrane, thus highlighting the protective anti-inflammatory function of CYP2J2 in the circulatory system.[7] There is still conflict in studies on the effects of EETs in relation to the cardiovascular system.[13][14] P450 enzymes have shown both positive and negative effects in the heart, and the production of EETs has been shown to produce vascular protective and vascular depressive mechanisms.[7] The over-expression of CYP2J2 enhances the activation ofmitoKATP, and is believed to confer a physiological benefit by altering the production ofreactive oxygen species.[7]
^Chen C, Wang DW (2013). "CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy".Current Topics in Medicinal Chemistry.13 (12):1454–1469.doi:10.2174/1568026611313120007.PMID23688135.
^Xu M, Ju W, Hao H, Wang G, Li P (Aug 2013). "Cytochrome P450 2J2: distribution, function, regulation, genetic polymorphisms and clinical significance".Drug Metabolism Reviews.45 (3):311–352.doi:10.3109/03602532.2013.806537.PMID23865864.S2CID22721300.
Zeldin DC, Foley J, Ma J, Boyle JE, Pascual JM, Moomaw CR, et al. (Nov 1996). "CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance".Molecular Pharmacology.50 (5):1111–1117.doi:10.1016/S0026-895X(25)09539-2.PMID8913342.
Zeldin DC, Foley J, Goldsworthy SM, Cook ME, Boyle JE, Ma J, et al. (Jun 1997). "CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance".Molecular Pharmacology.51 (6):931–943.doi:10.1124/mol.51.6.931.PMID9187259.
Bylund J, Finnström N, Oliw EH (Jul 1999). "Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles".Biochemical and Biophysical Research Communications.261 (1):169–174.Bibcode:1999BBRC..261..169B.doi:10.1006/bbrc.1999.1011.PMID10405341.
Gu J, Su T, Chen Y, Zhang QY, Ding X (Jun 2000). "Expression of biotransformation enzymes in human fetal olfactory mucosa: potential roles in developmental toxicity".Toxicology and Applied Pharmacology.165 (2):158–162.Bibcode:2000ToxAP.165..158G.doi:10.1006/taap.2000.8923.PMID10828211.
King LM, Ma J, Srettabunjong S, Graves J, Bradbury JA, Li L, et al. (Apr 2002). "Cloning of CYP2J2 gene and identification of functional polymorphisms".Molecular Pharmacology.61 (4):840–852.doi:10.1124/mol.61.4.840.PMID11901223.S2CID27031365.
Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y (Nov 2002). "Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole".Drug Metabolism and Disposition: The Biological Fate of Chemicals.30 (11):1240–1245.doi:10.1124/dmd.30.11.1240.PMID12386130.S2CID20029273.
Pucci L, Lucchesi D, Chirulli V, Penno G, Johansson I, Gervasi P, et al. (2004). "Cytochrome P450 2J2 polymorphism in healthy Caucasians and those with diabetes mellitus".American Journal of Pharmacogenomics.3 (5):355–358.doi:10.2165/00129785-200303050-00006.PMID14575523.S2CID41947830.
Xiao YF, Ke Q, Seubert JM, Bradbury JA, Graves J, Degraff LM, et al. (Dec 2004). "Enhancement of cardiac L-type Ca2+ currents in transgenic mice with cardiac-specific overexpression of CYP2J2".Molecular Pharmacology.66 (6):1607–1616.doi:10.1124/mol.104.004150.PMID15361551.S2CID17036714.
