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CYP2C8  -  cytochrome P450, family 2, subfamily C,...

Homo sapiens

Synonyms: CPC8, CYPIIC8, Cytochrome P450 2C8, Cytochrome P450 IIC2, Cytochrome P450 MP-12, ...
 
 
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Disease relevance of CYP2C8

 

Psychiatry related information on CYP2C8

 

High impact information on CYP2C8

 

Chemical compound and disease context of CYP2C8

 

Biological context of CYP2C8

 

Anatomical context of CYP2C8

 

Associations of CYP2C8 with chemical compounds

  • CYP2C8 is an important member of the CYP2C subfamily, which metabolizes both endogenous compounds (i.e., arachidonic acids and retinoic acid) and xenobiotics (e.g., paclitaxel) [14].
  • We show that submicromolar concentrations of dexamethasone enhance phenobarbital-mediated induction of CYP3A4, CYP2B6, and CYP2C8 mRNA in cultured human hepatocytes [23].
  • Dexamethasone (10 microM) treatment enhanced CYP2C8 mRNA (360 +/- 100%) and protein (274%) content, although this steroid had less effect on CYP2C9 and CYP2C19 transcripts (23 +/- 21% and 21 +/- 36%, respectively) and enzyme levels (55 and 143%, respectively) [24].
  • CYP2C9 appeared to form 12R-HETE and 13-HETE, whereas CYP2C8 formed 13-HETE, 11-HETE and 15-HETE as main monohydroxy metabolites [25].
  • Based on estimated total hepatic concentrations (or free plasma concentrations) of the drugs and the scaling model, one would expect in vivo in humans 80% (26%) and 13% (24%) inhibition of the metabolic clearance of CYP2C8 and CYP2C9 substrates by trimethoprim and sulfamethoxazole, respectively [26].
 

Regulatory relationships of CYP2C8

 

Other interactions of CYP2C8

  • Colchicine (COL) decreased both basal and rifampicin- and phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4 [28].
  • In summary, the present studies show that CAR, PXR, GR, and HNF4alpha can regulate CYP2C8 expression and identify specific cis-elements within the promoter that control these regulatory pathways [14].
  • In immunoblotting studies, the antibody bound strongly to recombinant CYP2C19 and weakly to recombinant CYP2C8 [29].
  • However, DMSO had little effect on CYP1A2, CYP2A6, and CYP2C8 [30].
  • After birth, hepatic CYP2D6 and CYP2C8/9 and CYP2C18/19 become active [31].
 

Analytical, diagnostic and therapeutic context of CYP2C8

References

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  2. The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension. Dreisbach, A.W., Japa, S., Sigel, A., Parenti, M.B., Hess, A.E., Srinouanprachanh, S.L., Rettie, A.E., Kim, H., Farin, F.M., Hamm, L.L., Lertora, J.J. Am. J. Hypertens. (2005) [Pubmed]
  3. Influence of clinicopathological variables on CYP protein expression in human liver. George, J., Byth, K., Farrell, G.C. J. Gastroenterol. Hepatol. (1996) [Pubmed]
  4. Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype. Kirchheiner, J., Thomas, S., Bauer, S., Tomalik-Scharte, D., Hering, U., Doroshyenko, O., Jetter, A., Stehle, S., Tsahuridu, M., Meineke, I., Brockmöller, J., Fuhr, U. Clin. Pharmacol. Ther. (2006) [Pubmed]
  5. Allelic variants of cytochromes P450 2C modify the risk for acute myocardial infarction. Yasar, U., Bennet, A.M., Eliasson, E., Lundgren, S., Wiman, B., De Faire, U., Rane, A. Pharmacogenetics (2003) [Pubmed]
  6. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. Taniguchi, R., Kumai, T., Matsumoto, N., Watanabe, M., Kamio, K., Suzuki, S., Kobayashi, S. J. Pharmacol. Sci. (2005) [Pubmed]
  7. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Daly, A.K., Aithal, G.P., Leathart, J.B., Swainsbury, R.A., Dang, T.S., Day, C.P. Gastroenterology (2007) [Pubmed]
  8. Antisense oligonucleotides against cytochrome P450 2C8 attenuate EDHF-mediated Ca(2+) changes and dilation in isolated resistance arteries. Bolz, S.S., Fisslthaler, B., Pieperhoff, S., De Wit, C., Fleming, I., Busse, R., Pohl, U. FASEB J. (2000) [Pubmed]
  9. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Chang, T.K., Yu, L., Maurel, P., Waxman, D.J. Cancer Res. (1997) [Pubmed]
  10. The disposition of oral amodiaquine in Papua New Guinean children with falciparum malaria. Hombhanje, F.W., Hwaihwanje, I., Tsukahara, T., Saruwatari, J., Nakagawa, M., Osawa, H., Paniu, M.M., Takahashi, N., Lum, J.K., Aumora, B., Masta, A., Sapuri, M., Kobayakawa, T., Kaneko, A., Ishizaki, T. British journal of clinical pharmacology. (2005) [Pubmed]
  11. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Hruska, M.W., Amico, J.A., Langaee, T.Y., Ferrell, R.E., Fitzgerald, S.M., Frye, R.F. British journal of clinical pharmacology. (2005) [Pubmed]
  12. A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin. Ishikawa, C., Ozaki, H., Nakajima, T., Ishii, T., Kanai, S., Anjo, S., Shirai, K., Inoue, I. J. Hum. Genet. (2004) [Pubmed]
  13. Dominant role of cytochrome P-450 2E1 in human hepatic microsomal oxidation of the CFC-substitute 1,1,1,2-tetrafluoroethane. Surbrook, S.E., Olson, M.J. Drug Metab. Dispos. (1992) [Pubmed]
  14. Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Ferguson, S.S., Chen, Y., LeCluyse, E.L., Negishi, M., Goldstein, J.A. Mol. Pharmacol. (2005) [Pubmed]
  15. The human CYP2C locus: a prototype for intergenic and exon repetition splicing events. Finta, C., Zaphiropoulos, P.G. Genomics (2000) [Pubmed]
  16. Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism. Shou, M., Lu, T., Krausz, K.W., Sai, Y., Yang, T., Korzekwa, K.R., Gonzalez, F.J., Gelboin, H.V. Eur. J. Pharmacol. (2000) [Pubmed]
  17. Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. Klose, T.S., Blaisdell, J.A., Goldstein, J.A. J. Biochem. Mol. Toxicol. (1999) [Pubmed]
  18. Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Jaakkola, T., Laitila, J., Neuvonen, P.J., Backman, J.T. Basic & clinical pharmacology & toxicology. (2006) [Pubmed]
  19. CYP2C8/9 mediate dapsone N-hydroxylation at clinical concentrations of dapsone. Winter, H.R., Wang, Y., Unadkat, J.D. Drug Metab. Dispos. (2000) [Pubmed]
  20. Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes. Rifkind, A.B., Lee, C., Chang, T.K., Waxman, D.J. Arch. Biochem. Biophys. (1995) [Pubmed]
  21. Detection of Human CYP2C8, CYP2C9, and CYP2J2 in Cardiovascular Tissues. Delozier, T.C., Kissling, G.E., Coulter, S.J., Dai, D., Foley, J.F., Bradbury, J.A., Murphy, E., Steenbergen, C., Zeldin, D.C., Goldstein, J.A. Drug Metab. Dispos. (2007) [Pubmed]
  22. Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8. García-Martín, E., Pizarro, R.M., Martínez, C., Gutierrez-Martín, Y., Pérez, G., Jover, R., Agúndez, J.A. Pharmacogenomics (2006) [Pubmed]
  23. Dexamethasone enhances constitutive androstane receptor expression in human hepatocytes: consequences on cytochrome P450 gene regulation. Pascussi, J.M., Gerbal-Chaloin, S., Fabre, J.M., Maurel, P., Vilarem, M.J. Mol. Pharmacol. (2000) [Pubmed]
  24. Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. Raucy, J.L., Mueller, L., Duan, K., Allen, S.W., Strom, S., Lasker, J.M. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  25. Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes. Bylund, J., Kunz, T., Valmsen, K., Oliw, E.H. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  26. Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Wen, X., Wang, J.S., Backman, J.T., Laitila, J., Neuvonen, P.J. Drug Metab. Dispos. (2002) [Pubmed]
  27. Effects of dexamethasone on mRNA abundance of nuclear receptors and hepatic nuclear receptor target genes in neonatal calves. Greger, D.L., Blum, J.W. Journal of animal physiology and animal nutrition (2007) [Pubmed]
  28. Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Dvorak, Z., Modriansky, M., Pichard-Garcia, L., Balaguer, P., Vilarem, M.J., Ulrichová, J., Maurel, P., Pascussi, J.M. Mol. Pharmacol. (2003) [Pubmed]
  29. Selective and potent inhibition of human CYP2C19 activity by a conformationally targeted antipeptide antibody. Schulz-Utermoehl, T., Mountfield, R.J., Madsen, K., Jørgensen, P.N., Hansen, K.T. Drug Metab. Dispos. (2000) [Pubmed]
  30. Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Busby, W.F., Ackermann, J.M., Crespi, C.L. Drug Metab. Dispos. (1999) [Pubmed]
  31. A review of developmental aspects of cytochrome P450. Oesterheld, J.R. Journal of child and adolescent psychopharmacology. (1998) [Pubmed]
  32. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. McFayden, M.C., Melvin, W.T., Murray, G.I. Biochem. Pharmacol. (1998) [Pubmed]
  33. Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1. Inoue, K., Inazawa, J., Suzuki, Y., Shimada, T., Yamazaki, H., Guengerich, F.P., Abe, T. Jpn. J. Hum. Genet. (1994) [Pubmed]
  34. Examination of 209 drugs for inhibition of cytochrome P450 2C8. Walsky, R.L., Gaman, E.A., Obach, R.S. Journal of clinical pharmacology. (2005) [Pubmed]
  35. Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. García-Martín, E., Martínez, C., Ladero, J.M., Agúndez, J.A. Molecular diagnosis & therapy. (2006) [Pubmed]
 
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