CYP2C9

Cytochrome P450, family 2, subfamily C, polypeptide 9
Ribbon diagram of CYP2C9, heme group visible at center. From PDB 1OG2.
Available structures PDB 1OG2, 1OG5, 1R9O
Identifiers
Symbols	CYP2C9; CPC9; CYP2C; CYP2C10; CYPIIC9; MGC149605; MGC88320; P450IIC9
External IDs	OMIM: 601130 MGI: 103238 HomoloGene: 110445 GeneCards: CYP2C9 Gene
Gene Ontology Molecular function • monooxygenase activity • monooxygenase activity • drug binding • steroid hydroxylase activity • electron carrier activity • oxidoreductase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • (S)-limonene 6-monooxygenase activity • (S)-limonene 7-monooxygenase activity • oxygen binding • heme binding • 4-hydroxyacetophenone monooxygenase activity • caffeine oxidase activity • metal ion binding Cellular component • endoplasmic reticulum • endoplasmic reticulum membrane • microsome • microsome • membrane Biological process • xenobiotic metabolic process • steroid metabolic process • monoterpenoid metabolic process • drug metabolic process • urea metabolic process • monocarboxylic acid metabolic process • drug catabolic process • exogenous drug catabolic process • cellular amide metabolic process • oxidation-reduction process • oxidative demethylation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1559	13095
Ensembl	ENSG00000138109	ENSMUSG00000003053
UniProt	P11712	Q3UEF2
RefSeq (mRNA)	NM_000771.3	NM_007815
RefSeq (protein)	NP_000762.2	NP_031841
Location (UCSC)	Chr 10: 96.7 – 96.75 Mb	Chr 19: 39.34 – 39.38 Mb
PubMed search	[1]	[2]

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

Function

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. 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

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[7]	ND	ND	ND	0.5-0.6	ND

CYP2C9 Ligands

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,^[8] tranylcypromine,^[9] phenethyl isothiocyanate,^[10] medroxyprogesterone acetate^[11] and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.^[12]

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.^[13]
• Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[13]
• 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.^[13]

Selected inducers, inhibitors and substrates of CYP2C9

Substrates	Inhibitors	Inducers
NSAIDs (analgesic, antipyretic, anti-inflammatory) celecoxib[13][14] lornoxicam[13][15] diclofenac[13][14] ibuprofen [13][14] naproxen[13][14] piroxicam[13][14] meloxicam[13][14] suprofen[13] phenytoin[13][14] (antiepileptic) fluvastatin[13][14] (statin) sulfonylureas (antidiabetic) glipizide[13][14] glibenclamide[13][14] glimepiride[13][14] tolbutamide[13][13] glyburide[13] angiotensin II receptor antagonists (in hypertension, diabetic nephropathy, CHF) irbesartan[13][14] losartan[13][14] S-warfarin[13][14] (anticoagulant) miconazole[14] (antifungal) sildenafil[14] (in erectile dysfunction) terbinafine[14] (antifungal) amitriptyline[13] (tricyclic antidepressant) fluoxetine[13] (SSRI antidepressant) nateglinide[13] (antidiabetic) rosiglitazone[13] (antidiabetic) tamoxifen[13] (SERM) torasemide[13] (loop diuretic)	Strong: fluconazole[13][14] (antifungal) amentoflavone[16] (constituent of Ginkgo biloba and St. John’s Wort[17]) sulfaphenazole[14] (antibacterial) Valproic acid[14] (anticonvulsant, mood-stabilizing) Moderate amiodarone[13] (antiarrhythmic) Unspecified potency antihistamines (H1-receptor antagonists) Cyclizine[18] Promethazine[18] Chloramphenicol[19] fenofibrate[13] (fibrate) flavones[12] flavonols[12] fluvastatin[13] (statin) fluvoxamine[13] (SSRI) isoniazid[13] (in tuberculosis) lovastatin[13] (statin) phenylbutazone[13] (NSAID) probenecid[13] (uricosuric) sertraline[13] (SSRI) sulfamethoxazole[13] (antibiotic) teniposide[13] (chemotherapeutic) voriconazole[13] (antifungal) zafirlukast[13] (leukotriene antagonist)	Strong: rifampicin[13][14] (bactericidal) secobarbital[13] (barbiturate)

See also

• Cytochrome P450 oxidase

References

1. ^ Romkes, Marjorie; Faletto, Michael B.; Blaisdell, Joyce A.; Raucy, Judy L.; Goldstein, Joyce A. (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, Kiyoshi; Inazawa, Johji; Suzuki, Yasuhiko; Shimada, Tsutomu; Yamazaki, Hiroshi; Guengerich, F. Peter; Abe, Tatsuo (1994). "Fluorescencein situ hybridization analysis of chromosomal localization of three human cytochrome P450 2C genes (CYP2C8, 2C9, and 2C10) at 10q24.1". The Japanese Journal of Human Genetics 39 (3): 337–43. doi:10.1007/BF01874052. PMID 7841444. 
3. ^ Rettie, Allan E.; Jones, Jeffrey P. (2005). "CLINICAL AND TOXICOLOGICAL RELEVANCE OF CYP2C9: Drug-Drug Interactions and Pharmacogenetics". Annual Review of Pharmacology and Toxicology 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. http://www.cypalleles.ki.se/cyp2c9.htm. ^{[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". Molecular diagnosis & therapy 10 (1): 29–40. PMID 16646575. 
6. ^ Rosemary, J.; Adithan, C. (2007). "The Pharmacogenetics of CYP2C9 and CYP2C19: Ethnic Variation and Clinical Significance". Current Clinical Pharmacology 2 (1): 93–109. doi:10.2174/157488407779422302. PMID 18690857. 
7. ^ Si, Dayong; Guo, Yingjie; Zhang, Yifan; Yang, Lei; Zhou, Hui; Zhong, Dafang (2004). "Identification of a novel variant CYP2C9 allele in Chinese". Pharmacogenetics 14 (7): 465–9. doi:10.1097/01.fpc.0000114749.08559.e4. PMID 15226678. 
8. ^ Bourrié, Martine; Meunier, Viviane; Berger, Yves; Fabre, Gérard (1999). "Role of Cytochrome P-4502C9 in Irbesartan Oxidation by Human Liver Microsomes". Drug Metabolism and Disposition 27 (2): 288–96. PMID 9929518. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9929518. 
9. ^ Salsali, Mahnaz; Holt, Andrew; Baker, Glen B. (2004). "Inhibitory Effects of the Monoamine Oxidase Inhibitor Tranylcypromine on the Cytochrome P450 Enzymes CYP2C19, CYP2C9, and CYP2D6". Cellular and Molecular Neurobiology 24 (1): 63–76. doi:10.1023/B:CEMN.0000012725.31108.4a. PMID 15049511. 
10. ^ Nakajima, Miki; Yoshida, Ryoko; Shimada, Noriaki; Yamazaki, Hiroshi; Yokoi, Tsuyoshi (2001). "Inhibition and Inactivation of Human Cytochrome P450 Isoforms by Phenethyl Isothiocyanate". Drug Metabolism and Disposition 29 (8): 1110–3. PMID 11454729. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11454729. 
11. ^ Zhang, Jiang-Wei; Liu, Yong; Li, Wei; Hao, Da-Cheng; Yang, Ling (2006). "Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes". European Journal of Clinical Pharmacology 62 (7): 497–502. doi:10.1007/s00228-006-0128-9. PMID 16645869. 
12. ^ ^{a b c} Si, D.; Wang, Y.; Zhou, Y.-H.; Guo, Y.; Wang, J.; Zhou, H.; Li, Z.-S.; Fawcett, J. P. (2008). "Mechanism of CYP2C9 Inhibition by Flavones and Flavonols". Drug Metabolism and Disposition 37 (3): 629–34. doi:10.1124/dmd.108.023416. PMID 19074529. 
13. ^ ^{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. http://medicine.iupui.edu/flockhart/table.htm. 
14. ^ ^{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)" (in Swedish). Swedish environmental classification of pharmaceuticals. http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352. 
15. ^ Guo, Y.; Zhang, Y; Wang, Y; Chen, X; Si, D; Zhong, D; Fawcett, JP; Zhou, H (2005). "ROLE OF CYP2C9 AND ITS VARIANTS (CYP2C9*3 AND CYP2C9*13) IN THE METABOLISM OF LORNOXICAM IN HUMANS". Drug Metabolism and Disposition 33 (6): 749–53. doi:10.1124/dmd.105.003616. PMID 15764711. 
16. ^ Kimura, Yuka; Ito, Hideyuki; Ohnishi, Ryoko; Hatano, Tsutomu (2010). "Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity". Food and Chemical Toxicology 48 (1): 429–35. doi:10.1016/j.fct.2009.10.041. PMID 19883715. 
17. ^ Pan, Xulin; Tan, Ninghua; Zeng, Guangzhi; Zhang, Yumei; Jia, Ruirui (2005). "Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B". Bioorganic & Medicinal Chemistry 13 (20): 5819–25. doi:10.1016/j.bmc.2005.05.071. PMID 16084098. 
18. ^ ^{a b} He, Nu; Zhang, Wen-Qi; Shockley, Dolores; Edeki, Timi (2002). "Inhibitory effects of H 1 -antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes". European Journal of Clinical Pharmacology 57 (12): 847–51. doi:10.1007/s00228-001-0399-0. PMID 11936702. 
19. ^ Park, J.-Y.; Kim, K.-A.; Kim, S.-L. (2003). "Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes". Antimicrobial Agents and Chemotherapy 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=253795. 

Further reading

• Goldstein, Joyce A.; De Morais, Sonia M. F. (1994). "Biochemistry and molecular biology of the human CYP2C subfamily". Pharmacogenetics 4 (6): 285–99. doi:10.1097/00008571-199412000-00001. PMID 7704034. 
• Miners, John O.; Birkett, Donald J. (1998). "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism". British Journal of Clinical Pharmacology 45 (6): 525–38. doi:10.1046/j.1365-2125.1998.00721.x. PMC 1873650. PMID 9663807. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1873650. 
• Smith, G.; Stubbins, M. J.; Harries, L. W.; Wolf, C. R. (1998). "Molecular genetics of the human cytochrome P450 monooxygenase superfamily". Xenobiotica 28 (12): 1129–65. doi:10.1080/004982598238868. PMID 9890157. 
• Henderson, R (2001). "Species differences in the metabolism of olefins: implications for risk assessment". Chemico-Biological Interactions 135-136: 53–64. doi:10.1016/S0009-2797(01)00170-3. PMID 11397381. 
• Xie, Hong-Guang; Prasad, Harish C; Kim, Richard B; Stein, C.Michael (2002). "CYP2C9 allelic variants: ethnic distribution and functional significance". Advanced Drug Delivery Reviews 54 (10): 1257–70. doi:10.1016/S0169-409X(02)00076-5. PMID 12406644. 
• Palkimas Jr, Michael P.; Skinner, Hillary M.; Gandhi, Pritesh J.; Gardner, Alice J. (2003). "Polymorphism Induced Sensitivity to Warfarin: A Review of the Literature". Journal of Thrombosis and Thrombolysis 15 (3): 205–12. doi:10.1023/B:THRO.0000011376.12309.af. PMID 14739630. 
• "Genetic Regulation of Warfarin Metabolism and Response". Seminars in Vascular Medicine 03 (3): 231–8. 2003. doi:10.1055/s-2003-44458. 
• García-Martín, E; Martínez, C; Ladero, JM; Agúndez, JA (2006). "Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals". Molecular diagnosis & therapy 10 (1): 29–40. PMID 16646575. 

External links

• PharmGKB: Annotated PGx Gene Information for CYP2C9
• SuperCYP: Database for Drug-Cytochrome-Interactions