CYP2J2
{{Short description|Gene of the species Homo sapiens}}
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Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene.{{cite journal | vauthors = Ma J, Ramachandran S, Fiedorek FT, Zeldin DC | title = Mapping of the CYP2J cytochrome P450 genes to human chromosome 1 and mouse chromosome 4 | journal = Genomics | volume = 49 | issue = 1 | pages = 152–155 | date = Apr 1998 | pmid = 9570962 | doi = 10.1006/geno.1998.5235 | url = https://zenodo.org/record/1229751 }}{{cite web | title = Entrez Gene: CYP2J2 cytochrome P450, family 2, subfamily J, polypeptide 2 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1573 }} CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.
Protein structure
• Hydrophobic binding domains
• F-G loop (containing non-conservative mutations) primary membrane binding motif
The protein also contains an N-terminal anchor.
= F-G loop =
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 the enzyme to interact with cellular membranes. Mutations to hydrophilic residues in the F-G loop alter the binding mechanism by changing insertion depth of the enzyme into the membrane.
Tissue distribution
CYP2J2 is expressed predominately in the heart and, to a lesser extent, in other tissues such as the liver, gastrointestinal tract, pancreas, lung, and central nervous system.
Function
CYP2J2 localizes to the endoplasmic reticulum and is thought to be a prominent enzyme responsible for metabolizing endogenous polyunsaturated fatty acids to signaling molecules.{{cite journal | vauthors = Chen C, Wang DW | title = CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy | journal = Current Topics in Medicinal Chemistry | volume = 13 | issue = 12 | pages = 1454–1469 | year = 2013 | pmid = 23688135 | doi = 10.2174/1568026611313120007 }} It metabolizes arachidonic acid to the following eicosatrienoic acid epoxides (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 metabolizes linoleic acid to 9,10-epoxy octadecenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).{{cite journal | vauthors = Westphal C, Konkel A, Schunck WH | title = CYP-eicosanoids--a new link between omega-3 fatty acids and cardiac disease? | journal = Prostaglandins & Other Lipid Mediators | volume = 96 | issue = 1–4 | pages = 99–108 | date = Nov 2011 | pmid = 21945326 | doi = 10.1016/j.prostaglandins.2011.09.001 | doi-access = free }}
CYP2J2, along with CYP219, CYP2C8, CYP2C9, and possibly CYP2S1 are the main producers of EETs and, very likely EEQs, EDPs, and the epoxides of linoleic acid.{{cite journal | vauthors = Wagner K, Vito S, Inceoglu B, Hammock BD | title = The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling | journal = Prostaglandins & Other Lipid Mediators | volume = 113-115 | pages = 2–12 | date = Oct 2014 | pmid = 25240260 | pmc = 4254344 | doi = 10.1016/j.prostaglandins.2014.09.001 }}
Animal studies
Animal model studies implicate the EETs, EDPs, and EEQs in regulating hypertension, the development of myocardial 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 (see epoxyeicosatrienoic acid, epoxydocosapentaenoic acid, and epoxygenase pages).{{cite journal | vauthors = Spector AA, Kim HY | title = Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism | journal = Biochimica et Biophysica Acta | volume = 1851 | issue = 4 | pages = 356–365 | date = Apr 2015 | pmid = 25093613 | pmc = 4314516 | doi = 10.1016/j.bbalip.2014.07.020 }} Vernolic and coronaric acids are potentially toxic, causing multiple organ failure and respiratory distress when injected into animals.
Human studies
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.{{cite journal | vauthors = Jiang JG, Chen CL, Card JW, Yang S, Chen JX, Fu XN, Ning YG, Zeldin DC, Wang DW | title = Cytochrome P450 Promotes the neoplastic phenotype of carcinoma cells and is Up-regulated in Human Tumors | journal = Cancer Research | volume = 65 | issue = 11 | pages = 4707–4715 | date = 2005 | pmid = 15930289 | doi = 10.1158/0008-5472.CAN-04-4173 | doi-access = free }} There was also a greater amount of CYP2J2 mRNA in various tumor types, including esophageal adenocarcinoma, breast carcinoma, and stomach 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.
Clinical significance
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 against apoptosis.{{cite journal | vauthors = Karkhanis A, Hong Y, Chan EC | title = Inhibition and inactivation of human CYP2J2: Implications in cardiac pathophysiology and opportunities in cancer therapy | journal = Biochemical Pharmacology | volume = 135 | pages = 12–21 | date = Jul 2017 | pmid = 28237650 | doi = 10.1016/j.bcp.2017.02.017 | s2cid = 43456597 | url = https://repository.hkbu.edu.hk/hkbu_staff_publication/6358 | access-date = 2019-07-05 | archive-date = 2017-11-12 | archive-url = https://web.archive.org/web/20171112125939/http://repository.hkbu.edu.hk/hkbu_staff_publication/6358/ | url-status = dead | url-access = subscription }}
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|date=April 2018}} CYP2J2 is readily expressed in the cardiac myocytes and endothelial 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. There is still conflict in studies on the effects of EETs in relation to the cardiovascular system.{{cite journal | vauthors = Xu M, Ju W, Hao H, Wang G, Li P | title = Cytochrome P450 2J2: distribution, function, regulation, genetic polymorphisms and clinical significance | journal = Drug Metabolism Reviews | volume = 45 | issue = 3 | pages = 311–352 | date = Aug 2013 | pmid = 23865864 | doi = 10.3109/03602532.2013.806537 | s2cid = 22721300 }}{{cite journal | vauthors = Askari A, Thomson SJ, Edin ML, Zeldin DC, Bishop-Bailey D | title = Roles of the epoxygenase CYP2J2 in the endothelium | journal = Prostaglandins & Other Lipid Mediators | volume = 107 | pages = 56–63 | date = Dec 2013 | pmid = 23474289 | pmc = 3711961 | doi = 10.1016/j.prostaglandins.2013.02.003 }} 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. The over-expression of CYP2J2 enhances the activation of mitoKATP, and is believed to confer a physiological benefit by altering the production of reactive oxygen species.
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References
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Further reading
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- {{cite journal | vauthors = Scarborough PE, Ma J, Qu W, Zeldin DC | title = P450 subfamily CYP2J and their role in the bioactivation of arachidonic acid in extrahepatic tissues | journal = Drug Metabolism Reviews | volume = 31 | issue = 1 | pages = 205–234 | date = Feb 1999 | pmid = 10065373 | doi = 10.1081/DMR-100101915 | url = https://zenodo.org/record/1236070 }}
- {{cite journal | vauthors = Capdevila JH, Falck JR, Harris RC | title = Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase | journal = Journal of Lipid Research | volume = 41 | issue = 2 | pages = 163–181 | date = Feb 2000 | pmid = 10681399 | doi = 10.1016/S0022-2275(20)32049-6 | author2-link = John R. Falck | doi-access = free }}
- {{cite journal | vauthors = Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC | title = Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart | journal = The Journal of Biological Chemistry | volume = 271 | issue = 7 | pages = 3460–3468 | date = Feb 1996 | pmid = 8631948 | doi = 10.1074/jbc.271.7.3460 | doi-access = free }}
- {{cite journal | vauthors = Zeldin DC, Foley J, Ma J, Boyle JE, Pascual JM, Moomaw CR, Tomer KB, Steenbergen C, Wu S | title = CYP2J subfamily P450s in the lung: expression, localization, and potential functional significance | journal = Molecular Pharmacology | volume = 50 | issue = 5 | pages = 1111–1117 | date = Nov 1996 | pmid = 8913342 }}
- {{cite journal | vauthors = Zeldin DC, Foley J, Boyle JE, Moomaw CR, Tomer KB, Parker C, Steenbergen C, Wu S | title = Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human and rat pancreas | journal = Endocrinology | volume = 138 | issue = 3 | pages = 1338–1346 | date = Mar 1997 | pmid = 9048644 | doi = 10.1210/endo.138.3.4970 | doi-access = free }}
- {{cite journal | vauthors = Zeldin DC, Foley J, Goldsworthy SM, Cook ME, Boyle JE, Ma J, Moomaw CR, Tomer KB, Steenbergen C, Wu S | title = CYP2J subfamily cytochrome P450s in the gastrointestinal tract: expression, localization, and potential functional significance | journal = Molecular Pharmacology | volume = 51 | issue = 6 | pages = 931–943 | date = Jun 1997 | pmid = 9187259 | doi = 10.1124/mol.51.6.931 }}
- {{cite journal | vauthors = Bylund J, Finnström N, Oliw EH | title = Gene expression of a novel cytochrome P450 of the CYP4F subfamily in human seminal vesicles | journal = Biochemical and Biophysical Research Communications | volume = 261 | issue = 1 | pages = 169–174 | date = Jul 1999 | pmid = 10405341 | doi = 10.1006/bbrc.1999.1011 }}
- {{cite journal | vauthors = Gu J, Su T, Chen Y, Zhang QY, Ding X | title = Expression of biotransformation enzymes in human fetal olfactory mucosa: potential roles in developmental toxicity | journal = Toxicology and Applied Pharmacology | volume = 165 | issue = 2 | pages = 158–162 | date = Jun 2000 | pmid = 10828211 | doi = 10.1006/taap.2000.8923 }}
- {{cite journal | vauthors = King LM, Ma J, Srettabunjong S, Graves J, Bradbury JA, Li L, Spiecker M, Liao JK, Mohrenweiser H, Zeldin DC | title = Cloning of CYP2J2 gene and identification of functional polymorphisms | journal = Molecular Pharmacology | volume = 61 | issue = 4 | pages = 840–852 | date = Apr 2002 | pmid = 11901223 | doi = 10.1124/mol.61.4.840 | s2cid = 27031365 }}
- {{cite journal | vauthors = Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y | title = Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole | journal = Drug Metabolism and Disposition: the Biological Fate of Chemicals | volume = 30 | issue = 11 | pages = 1240–1245 | date = Nov 2002 | pmid = 12386130 | doi = 10.1124/dmd.30.11.1240 | s2cid = 20029273 }}
- {{cite journal | vauthors = Marden NY, Fiala-Beer E, Xiang SH, Murray M | title = Role of activator protein-1 in the down-regulation of the human CYP2J2 gene in hypoxia | journal = The Biochemical Journal | volume = 373 | issue = Pt 3 | pages = 669–680 | date = Aug 2003 | pmid = 12737630 | pmc = 1223548 | doi = 10.1042/BJ20021903 }}
- {{cite journal | vauthors = Pucci L, Lucchesi D, Chirulli V, Penno G, Johansson I, Gervasi P, Del Prato S, Longo V | title = Cytochrome P450 2J2 polymorphism in healthy Caucasians and those with diabetes mellitus | journal = American Journal of Pharmacogenomics : Genomics-related Research in Drug Development and Clinical Practice | volume = 3 | issue = 5 | pages = 355–358 | year = 2004 | pmid = 14575523 | doi = 10.2165/00129785-200303050-00006 | s2cid = 41947830 }}
- {{cite journal | vauthors = Seubert J, Yang B, Bradbury JA, Graves J, Degraff LM, Gabel S, Gooch R, Foley J, Newman J, Mao L, Rockman HA, Hammock BD, Murphy E, Zeldin DC | title = Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway | journal = Circulation Research | volume = 95 | issue = 5 | pages = 506–514 | date = Sep 2004 | pmid = 15256482 | doi = 10.1161/01.RES.0000139436.89654.c8 | doi-access = free }}
- {{cite journal | vauthors = Xiao YF, Ke Q, Seubert JM, Bradbury JA, Graves J, Degraff LM, Falck JR, Krausz K, Gelboin HV, Morgan JP, Zeldin DC | title = Enhancement of cardiac L-type Ca2+ currents in transgenic mice with cardiac-specific overexpression of CYP2J2 | journal = Molecular Pharmacology | volume = 66 | issue = 6 | pages = 1607–1616 | date = Dec 2004 | pmid = 15361551 | doi = 10.1124/mol.104.004150 | author9-link = Harry Gelboin | s2cid = 17036714 }}
- {{cite journal | vauthors = Spiecker M, Darius H, Hankeln T, Soufi M, Sattler AM, Schaefer JR, Node K, Börgel J, Mügge A, Lindpaintner K, Huesing A, Maisch B, Zeldin DC, Liao JK | title = Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2 | journal = Circulation | volume = 110 | issue = 15 | pages = 2132–2136 | date = Oct 2004 | pmid = 15466638 | pmc = 2633457 | doi = 10.1161/01.CIR.0000143832.91812.60 }}
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