CYP2C9

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Cytochrome P450, family 2, subfamily C, polypeptide 9
CYP2C9 1OG2.png
Ribbon diagram of CYP2C9, heme group visible at center. From PDB 1OG2.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CYP2C9 ; CPC9; CYP2C; CYP2C10; CYPIIC9; P450IIC9
External IDs OMIM601130 MGI103238 HomoloGene128042 ChEMBL: 3397 GeneCards: CYP2C9 Gene
EC number 1.14.13.48, 1.14.13.49, 1.14.13.80
RNA expression pattern
PBB GE CYP2C9 214421 x at tn.png
PBB GE CYP2C9 216025 x at tn.png
PBB GE CYP2C9 216661 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1559 72082
Ensembl ENSG00000138109 ENSMUSG00000025002
UniProt P11712 Q9D816
RefSeq (mRNA) NM_000771 NM_028089
RefSeq (protein) NP_000762 NP_082365
Location (UCSC) Chr 10:
96.7 – 96.75 Mb
Chr 19:
39.01 – 39.04 Mb
PubMed search [1] [2]

Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene.[1][2]

Function[edit]

CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes (data only for antifungal). Some 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compound such as arachidonic acid, 5-hydroxytryptamine, and linoleic acid.[3]

Pharmacogenomics[edit]

Genetic polymorphism exists for CYP2C9 expression because the CYP2C9 gene is highly polymorphic. More than 50 single nucleotide polymorphisms (SNPs) have been described in the regulatory and coding regions of the CYP2C9 gene,[4] some of them are associated with reduced enzyme activity compared with wild type in vitro.[citation needed]

Multiple in vivo studies also show that several mutant CYP2C9 genotypes are associated with significant reduction of in metabolism and daily dose requirements of selected CYP2C9 substrate. In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses.[5][6]

Allele frequencies(%) of CYP2C9 polymorphism

African-American Black-African Pygmy Asian Caucasian
CYP2C9*2 2.9 0-4.3 0 0-0.1 8-19
CYP2C9*3 2.0 0-2.3 0 1.1-3.6 3.3-16.2
CYP2C9*5 0-1.7 0.8-1.8 ND 0 0
CYP2C9*6 0.6 2.7 ND 0 0
CYP2C9*7 0 0 6 0 0
CYP2C9*8 1.9 8.6 4 0 0
CYP2C9*9 13 15.7 22 0 0.3
CYP2C9*11 1.4-1.8 2.7 6 0 0.4-1.0
CYP2C9*13 ND ND ND 0.19-0.45 ND

CYP2C9 Ligands[edit]

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,[7][8] phenethyl isothiocyanate,[9] medroxyprogesterone acetate[10] and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[11]

Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C9 can be classified by their potency, such as:

  • Strong being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[12]
  • Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.[12]
  • Weak being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.[12]
Selected inducers, inhibitors and substrates of CYP2C9
Substrates Inhibitors Inducers
Strong:

Moderate

Unspecified potency

Strong:

See also[edit]

References[edit]

  1. ^ Romkes M, Faletto MB, Blaisdell JA, Raucy JL, Goldstein JA (April 1991). "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily". Biochemistry 30 (13): 3247–55. doi:10.1021/bi00227a012. PMID 2009263. 
  2. ^ Inoue K, Inazawa J, Suzuki Y, Shimada T, Yamazaki H, Guengerich FP, Abe T (September 1994). "Fluorescence in situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1". Jpn. J. Hum. Genet. 39 (3): 337–43. doi:10.1007/BF01874052. PMID 7841444. 
  3. ^ Rettie AE, Jones JP (2005). "Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics". Annu. Rev. Pharmacol. Toxicol. 45: 477–94. doi:10.1146/annurev.pharmtox.45.120403.095821. PMID 15822186. 
  4. ^ Sim, Sarah C (2 May 2011). "CYP2C9 allele nomenclature". Cytochrome P450 (CYP) Allele Nomenclature Committee. [self-published source?]
  5. ^ García-Martín E, Martínez C, Ladero JM, Agúndez JA (2006). "Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals". Mol Diagn Ther 10 (1): 29–40. doi:10.1007/BF03256440. PMID 16646575. 
  6. ^ Rosemary J, Adithan C (January 2007). "The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance". Curr Clin Pharmacol 2 (1): 93–109. doi:10.2174/157488407779422302. PMID 18690857. 
  7. ^ Bourrié M, Meunier V, Berger Y, Fabre G (February 1999). "Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes". Drug Metab. Dispos. 27 (2): 288–96. PMID 9929518. 
  8. ^ Salsali M, Holt A, Baker GB (February 2004). "Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6". Cell. Mol. Neurobiol. 24 (1): 63–76. doi:10.1023/B:CEMN.0000012725.31108.4a. PMID 15049511. 
  9. ^ Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T (August 2001). "Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate". Drug Metab. Dispos. 29 (8): 1110–3. PMID 11454729. 
  10. ^ Zhang JW, Liu Y, Li W, Hao DC, Yang L (July 2006). "Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes". Eur. J. Clin. Pharmacol. 62 (7): 497–502. doi:10.1007/s00228-006-0128-9. PMID 16645869. 
  11. ^ a b c d e Si D, Wang Y, Zhou YH, Guo Y, Wang J, Zhou H, Li ZS, Fawcett JP (March 2009). "Mechanism of CYP2C9 inhibition by flavones and flavonols". Drug Metab. Dispos. 37 (3): 629–34. doi:10.1124/dmd.108.023416. PMID 19074529. 
  12. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 
  13. ^ a b c d e f g h i j k l m n o p q r s t u FASS (drug formulary): "Facts for prescribers (Fakta för förskrivare)". Swedish environmental classification of pharmaceuticals (in Swedish). 
  14. ^ Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP, Zhou H (June 2005). "Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans". Drug Metab. Dispos. 33 (6): 749–53. doi:10.1124/dmd.105.003616. PMID 15764711. 
  15. ^ http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3825&loc=ec_rcs#x301
  16. ^ Stout, S. M.; Cimino, N. M. (2014). "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: A systematic review". Drug Metabolism Reviews 46 (1): 86–95. doi:10.3109/03602532.2013.849268. PMID 24160757.  edit
  17. ^ Kimura Y, Ito H, Ohnishi R, Hatano T (January 2010). "Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity". Food Chem. Toxicol. 48 (1): 429–35. doi:10.1016/j.fct.2009.10.041. PMID 19883715. 
  18. ^ Pan X, Tan N, Zeng G, Zhang Y, Jia R (October 2005). "Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B". Bioorg. Med. Chem. 13 (20): 5819–25. doi:10.1016/j.bmc.2005.05.071. PMID 16084098. 
  19. ^ a b He N, Zhang WQ, Shockley D, Edeki T (February 2002). "Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". Eur. J. Clin. Pharmacol. 57 (12): 847–51. doi:10.1007/s00228-001-0399-0. PMID 11936702. 
  20. ^ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrob. Agents Chemother. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103. 

Further reading[edit]

External links[edit]