| 释义 |
- CYP2C8 ligands
- Epoxygenase activity
- See also
- References
- External links
- Further reading
{{Infobox_gene}}Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.[1] CYP2C8 ligands Following is a table of selected substrates, inducers and inhibitors of 2C8. Inhibitors of CYP2C8 can be classified by their potency, such as: - Strong inhibitor being one that causes at least a five-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[2]
- Moderate inhibitor being one that causes at least a two-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[2]
- Weak inhibitor being one that causes at least a 1.25-fold but less than two-fold increase in the plasma AUC values, or 20-50% decrease in clearance.[2]
Selected inducers, inhibitors and substrates of CYP2C8| Substrates | Inhibitors | Inducers |
|---|
- amodiaquine[2] (antimalarial, anti-inflammatory)
- cerivastatin[2] (statin)
- enzalutamide (antiandrogen)
- paclitaxel[2] (chemotherapeutic)
- repaglinide[2] (antidiabetic)
- torasemide[2] (loop diuretic)
- sorafenib[2] (tyrosine kinase inhibitor)
- rosiglitazone (antidiabetic) - converted to active metabolites[3]
- buprenorphine (semisynthetic opioid)
- polyunsaturated fatty acids
- montelukast (leukotriene receptor antagonist)
| Strong- gemfibrozil[2] (hypolipidemic)
Moderate- trimethoprim[2] (antibiotic)
Unspecified potency- thiazolidinediones[2] (antidiabetic)
- montelukast[2] (leukotriene receptor antagonist)
- quercetin[2] (antiinflammatory)
| Unspecified potency- rifampicin[2] (antibiotic)
| |
Where classes of agents are listed, there may be exceptions within the class. Epoxygenase activity CYP2C8 also possesses epoxygenase activitiy: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes: 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosohexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[4][5][6] Along with CYP2C8, CYP2C9, CYP2C19, CYP2J2, and possibly CYP2S1 are the main producers of EETs and, very likely, EEQs, EDPs, and the epoxides of linoleic acid.[7][8] See also - Cytochrome P450 oxidase
- Epoxygenase
References 1. ^{{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 }}
2. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 {{cite web |author=Flockhart DA |title=Drug Interactions: Cytochrome P450 Drug Interaction Table |publisher=Indiana University School of Medicine |year=2007 |url=http://medicine.iupui.edu/flockhart/table.htm}} Retrieved on July 2011
3. ^Chapter 26 in: {{cite book |author1=Rod Flower |author2=Humphrey P. Rang |author3=Maureen M. Dale |author4=Ritter, James M. |title=Rang & Dale's pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |pages= |isbn=0-443-06911-5 |oclc= |doi= |accessdate=}}
4. ^{{cite journal | vauthors = Fleming I | title = The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease | journal = Pharmacological Reviews | volume = 66 | issue = 4 | pages = 1106–40 | date = October 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 }}
5. ^{{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 = October 2014 | pmid = 25240260 | doi = 10.1016/j.prostaglandins.2014.09.001 | pmc=4254344}}
6. ^{{cite journal | vauthors = Fischer R, Konkel A, Mehling H, Blossey K, Gapelyuk A, Wessel N, von Schacky C, Dechend R, Muller DN, Rothe M, Luft FC, Weylandt K, Schunck WH | title = Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway | journal = Journal of Lipid Research | volume = 55 | issue = 6 | pages = 1150–1164 | date = March 2014 | pmid = 24634501 | doi = 10.1194/jlr.M047357 | pmc=4031946}}
7. ^{{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 = 356–65 | date = April 2015 | pmid = 25093613 | doi = 10.1016/j.bbalip.2014.07.020 | pmc=4314516}}
8. ^{{cite journal | vauthors = Shahabi P, Siest G, Meyer UA, Visvikis-Siest S | title = Human cytochrome P450 epoxygenases: variability in expression and role in inflammation-related disorders | journal = Pharmacology & Therapeutics | volume = 144 | issue = 2 | pages = 134–61 | date = November 2014 | pmid = 24882266 | doi = 10.1016/j.pharmthera.2014.05.011 }}
External links- {{UCSC gene info|CYP2C8}}
Further reading {{refbegin|33em}}- {{cite journal | vauthors = Goldstein JA, de Morais SM | title = Biochemistry and molecular biology of the human CYP2C subfamily | journal = Pharmacogenetics | volume = 4 | issue = 6 | pages = 285–99 | date = Dec 1994 | pmid = 7704034 | doi = 10.1097/00008571-199412000-00001 }}
- {{cite journal | vauthors = Smith G, Stubbins MJ, Harries LW, Wolf CR | title = Molecular genetics of the human cytochrome P450 monooxygenase superfamily | journal = Xenobiotica | volume = 28 | issue = 12 | pages = 1129–65 | date = Dec 1998 | pmid = 9890157 | doi = 10.1080/004982598238868 }}
- {{cite journal | vauthors = García-Martín E, Martínez C, Ladero JM, Agúndez JA | title = Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals | journal = Molecular Diagnosis & Therapy | volume = 10 | issue = 1 | pages = 29–40 | year = 2007 | pmid = 16646575 | doi = 10.1007/BF03256440 }}
- {{cite journal | vauthors = Ged C, Beaune P | title = Isolation of the human cytochrome P-450 IIC8 gene: multiple glucocorticoid responsive elements in the 5' region | journal = Biochimica et Biophysica Acta | volume = 1088 | issue = 3 | pages = 433–5 | date = Mar 1991 | pmid = 1707679 | doi = 10.1016/0167-4781(91)90138-c }}
- {{cite journal | vauthors = Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA | title = Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily | journal = Biochemistry | volume = 30 | issue = 13 | pages = 3247–55 | date = Apr 1991 | pmid = 2009263 | doi = 10.1021/bi00227a012 }}
- {{cite journal | vauthors = Kolyada AY | title = Sequence of a human liver cytochrome P-450 cDNA clone | journal = Nucleic Acids Research | volume = 18 | issue = 18 | pages = 5550 | date = Sep 1990 | pmid = 2216732 | pmc = 332242 | doi = 10.1093/nar/18.18.5550 }}
- {{cite journal | vauthors = Shephard EA, Phillips IR, Santisteban I, Palmer CN, Povey S | title = Cloning, expression and chromosomal localization of a member of the human cytochrome P450IIC gene sub-family | journal = Annals of Human Genetics | volume = 53 | issue = Pt 1 | pages = 23–31 | date = Jan 1989 | pmid = 2729895 | doi = 10.1111/j.1469-1809.1989.tb01119.x }}
- {{cite journal | vauthors = Ged C, Umbenhauer DR, Bellew TM, Bork RW, Srivastava PK, Shinriki N, Lloyd RS, Guengerich FP | title = Characterization of cDNAs, mRNAs, and proteins related to human liver microsomal cytochrome P-450 (S)-mephenytoin 4'-hydroxylase | journal = Biochemistry | volume = 27 | issue = 18 | pages = 6929–40 | date = Sep 1988 | pmid = 3196692 | doi = 10.1021/bi00418a039 }}
- {{cite journal | vauthors = Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH | title = Characterization of multiple human cytochrome P-450 1 cDNAs. The chromosomal localization of the gene and evidence for alternate RNA splicing | journal = The Journal of Biological Chemistry | volume = 262 | issue = 33 | pages = 16072–9 | date = Nov 1987 | pmid = 3500169 | doi = }}
- {{cite journal | vauthors = Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ | title = cDNA and amino acid sequences of two members of the human P450IIC gene subfamily | journal = Nucleic Acids Research | volume = 15 | issue = 23 | pages = 10053–4 | date = Dec 1987 | pmid = 3697070 | pmc = 306558 | doi = 10.1093/nar/15.23.10053 }}
- {{cite journal | vauthors = Zeldin DC, DuBois RN, Falck JR, Capdevila JH | title = Molecular cloning, expression and characterization of an endogenous human cytochrome P450 arachidonic acid epoxygenase isoform | journal = Archives of Biochemistry and Biophysics | volume = 322 | issue = 1 | pages = 76–86 | date = Sep 1995 | pmid = 7574697 | doi = 10.1006/abbi.1995.1438 }}
- {{cite journal | vauthors = Inoue K, Inazawa J, Suzuki Y, Shimada T, Yamazaki H, Guengerich FP, Abe T | title = Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1 | journal = The Japanese Journal of Human Genetics | volume = 39 | issue = 3 | pages = 337–43 | date = Sep 1994 | pmid = 7841444 | doi = 10.1007/BF01874052 }}
- {{cite journal | vauthors = Gray IC, Nobile C, Muresu R, Ford S, Spurr NK | title = A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24 | journal = Genomics | volume = 28 | issue = 2 | pages = 328–32 | date = Jul 1995 | pmid = 8530044 | doi = 10.1006/geno.1995.1149 }}
- {{cite journal | vauthors = Wormhoudt LW, Ploemen JH, de Waziers I, Commandeur JN, Beaune PH, van Bladeren PJ, Vermeulen NP | title = Inter-individual variability in the oxidation of 1,2-dibromoethane: use of heterologously expressed human cytochrome P450 and human liver microsomes | journal = Chemico-Biological Interactions | volume = 101 | issue = 3 | pages = 175–92 | date = Sep 1996 | pmid = 8870687 | doi = 10.1016/0009-2797(96)03723-4 }}
- {{cite journal | vauthors = McFayden MC, Melvin WT, Murray GI | title = Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain | journal = Biochemical Pharmacology | volume = 55 | issue = 6 | pages = 825–30 | date = Mar 1998 | pmid = 9586955 | doi = 10.1016/S0006-2952(97)00516-9 }}
- {{cite journal | vauthors = Macé K, Bowman ED, Vautravers P, Shields PG, Harris CC, Pfeifer AM | title = Characterisation of xenobiotic-metabolising enzyme expression in human bronchial mucosa and peripheral lung tissues | journal = European Journal of Cancer | volume = 34 | issue = 6 | pages = 914–20 | date = May 1998 | pmid = 9797707 | doi = 10.1016/S0959-8049(98)00034-3 }}
- {{cite journal | vauthors = Klose TS, Blaisdell JA, Goldstein JA | title = Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs | journal = Journal of Biochemical and Molecular Toxicology | volume = 13 | issue = 6 | pages = 289–95 | year = 1999 | pmid = 10487415 | doi = 10.1002/(SICI)1099-0461(1999)13:6<289::AID-JBT1>3.0.CO;2-N }}
- {{cite journal | vauthors = Finta C, Zaphiropoulos PG | title = The human CYP2C locus: a prototype for intergenic and exon repetition splicing events | journal = Genomics | volume = 63 | issue = 3 | pages = 433–8 | date = Feb 2000 | pmid = 10704292 | doi = 10.1006/geno.1999.6063 }}
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