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CYP2C9

From Wikipedia, the free encyclopedia

CYP2C9
Available structures
PDBHuman UniProt search:PDBeRCSB
Identifiers
AliasesCYP2C9,CPC9, CYP2C, CYP2C10, CYPIIC9, P450IIC9, cytochrome P450 family 2 subfamily C member 9, Cytochrome P450 2C9, P450-2C9
External IDsOMIM:601130;MGI:1919553;HomoloGene:133566;GeneCards:CYP2C9;OMA:CYP2C9 - orthologs
EC number1.14.14.51
Orthologs
SpeciesHumanMouse
Entrez

1559

72303

Ensembl

ENSG00000138109

ENSMUSG00000067231

UniProt

P11712

n/a

RefSeq (mRNA)

NM_000771

NM_028191

RefSeq (protein)

NP_000762

n/a

Location (UCSC)Chr 10: 94.94 – 94.99 MbChr 19: 39.05 – 39.08 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cytochrome P450 family 2 subfamily C member 9(abbreviatedCYP2C9) is anenzymeprotein.The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by theCYP2C9gene.[5][6]The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.[7]

Function

[edit]

CYP2C9 is a crucialcytochrome P450enzyme, which plays a significant role in the metabolism, by oxidation, of both xenobiotic and endogenous compounds.[7]CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. The protein is mainly expressed in theliver,duodenum,andsmall intestine.[7]About 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such aswarfarinandphenytoin,and other routinely prescribed drugs such asacenocoumarol,tolbutamide,losartan,glipizide,and somenonsteroidal anti-inflammatory drugs.By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to itsepoxygenaseactivity, variouspolyunsaturated fatty acids,converting these fatty acids to a wide range of biologically active products.[8][9]

In particular, CYP2C9 metabolizesarachidonic acidto the followingeicosatrienoic acid epoxide(EETs)stereoisomersets: 5R,6S-epoxy-8Z,11Z,14Z-eicosatetraenoic and 5S,6R-epoxy-8Z,11Z,14Z-eicosatetraenoic acids; 11R,12S-epoxy-8Z,11Z,14Z-eicosatetraenoic and 11S,12R-epoxy-5Z,8Z,14Z-eicosatetraenoic acids; and 14R,15S-epoxy-5Z,8Z,11Z-eicosatetraenoic and 14S,15R-epoxy-5Z,8Z,11Z-eicosatetraenoic acids. It likewise metabolizesdocosahexaenoic acidtoepoxydocosapentaenoic acids(EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) andeicosapentaenoic acidtoepoxyeicosatetraenoic acids(EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers).[10]Animal models and a limited number of human studies implicate these epoxides in reducinghypertension;protecting againstmyocardial infarctionand other insults to the heart; promoting the growth and metastasis of certain cancers; inhibitinginflammation;stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulatingneurohormonerelease and blocking pain perception (seeepoxyeicosatrienoic acidandepoxygenase).[9]

In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of another product of CYP450 enzymes (e.g.CYP4A1,CYP4A11,CYP4F2,CYP4F3A,andCYP4F3B) viz.,20-Hydroxyeicosatetraenoic acid(20-HETE), principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see20-Hydroxyeicosatetraenoic acid,epoxyeicosatetraenoic acid,andepoxydocosapentaenoic acidsections on activities and clinical significance). Such studies also indicate that theeicosapentaenoic acidsand EEQs are:1)more potent than EETs in decreasing hypertension and pain perception;2)more potent than or equal in potency to the EETs in suppressing inflammation; and3)act oppositely from the EETs in that they inhibitangiogenesis,endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems.[11][12][13][14]Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans, and in humans is by far the most prominent change in the profile ofpolyunsaturated fatty acidsmetabolites caused by dietary omega-3 fatty acids.[11][14][15]

CYP2C9 may also metabolizelinoleic acidto the potentially very toxic products,coronaric acid(also termed leukotoxin) andvernolic acid(also termed isoleukotoxin); these linoleic acid epoxides causemultiple organ failureandacute respiratory distressin animal models and may contribute to these syndromes in humans.[9]

Pharmacogenomics

[edit]

TheCYP2C9gene is highly polymorphic.[16]At least 20single nucleotide polymorphisms(SNPs) have been reported to have functional evidence of altered enzyme activity.[16]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.[17][18]Information about how human genetic variation of CYP2C9 affects response to medications can be found in databases such PharmGKB,[19]Clinical Pharmacogenetics Implementation Consortium (CPIC).[20]

The label CYP2C9*1 is assigned by thePharmacogene Variation Consortium(PharmVar) to the most commonly observed human gene variant.[21]Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label.[22][23]The two most well-characterized variant alleles are CYP2C9*2 (NM_000771.3:c.430C>T, p.Arg144Cys, rs1799853) and CYP2C9*3 (NM_000771.3:c.1075A>C, p. Ile359Leu, rs1057910),[24]causing reductions in enzyme activity of 30% and 80%, respectively.[16]

Metabolizer phenotypes

[edit]

On the basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. The carriers of homozygous CYP2C9*1 variant, i.e. of the *1/*1 genotype, are designated extensive metabolizers (EM), or normal metabolizers.[25]The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. just one of these alleles (*1/*2, *1/*3) are designated intermediate metabolizers (IM), and those carrying two of these alleles, i.e. homozygous (*2/*3, *2/*2 or *3/*3) – poor metabolizers (PM).[26][27]As a result, the metabolic ratio – the ratio of unchanged drug to metabolite – is higher in PMs.

A study of the ability to metabolize warfarin among the carriers of the most well-characterized CYP2C9 genotypes (*1, *2 and *3), expressed as a percentage of the mean dose in patients with wild-type alleles (*1/*1), concluded that the mean warfarin maintenance dose was 92% in *1/*2, 74% in *1/*3, 63% in *2/*3, 61% in *2/*2 and 34% in 3/*3.[28]

CYP2C9*3 reflects anIle359-Leu(I359L) change in theamino acidsequence,[29]and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin.[30]Its prevalence varies with race as:

Allele frequencies (%) of CYP2C9 polymorphism
African-American Black-African Pygmy Asian Caucasian
CYP2C9*3 2.0 0–2.3 0 1.1–3.6 3.3–16.2

Test panels of variant alleles

[edit]

The Association for Molecular Pathology Pharmacogenomics (PGx) Working Group in 2019 has recommended a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) to be included in assays for CYP2C9 testing.

CYP2C9 variant alleles recommended as Tier 1 by the PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. This recommendation was based on their well-established functional effects on CYP2C9 activity and drug response availability of reference materials, and their appreciable allele frequencies in major ethnic groups.

The following CYP2C9 alleles are recommended for inclusion in tier 2: CYP2C9*12, *13, and *15.[16]

CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p. Leu90Pro, rs72558187).[16]CYP2C9*13 prevalence is approximately 1% in the Asian population,[31]but in Caucasians this variant prevalence is almost zero.[32]This variant is caused by a T269C mutation in the CYP2C9 gene which in turn results in the substitution of leucine at position-90 with proline (L90P) at the product enzyme protein. This residue is near the access point for substrates and the L90P mutation causes lower affinity and hence slower metabolism of several drugs that are metabolized CYP2C9 by such asdiclofenacandflurbiprofen.[31]However, this variant is not included in the tier 1 recommendations of the PGx Working Group because of its very low multiethnic minor allele frequency and a lack of currently available reference materials.[16]As of 2020the evidence level for CYP2C9*13 in thePharmVardatabase is limited, comparing to the tier 1 alleles, for which the evidence level is definitive.[21]

Additional variants

[edit]

Not all clinically significant genetic variant alleles have been registered byPharmVar.For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3.[33]Allele A (23% global frequency) is associated with a decreased dose of warfarin as compared to the allele G (77% global frequency). Another variant, rs4917639, according to a 2009 study, has a strong effect on warfarin sensitivity, almost the same as if CYP2C9*2 and CYP2C9*3 were combined into a single allele.[34]The C allele at rs4917639 has 19% global frequency. Patients with the CC or CA genotype may require decreased dose of warfarin as compared to patients with the wild-type AA genotype.[35]Another variant, rs7089580 with T allele having 14% global frequency, is associated with increased CYP2C9 gene expression. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels compared to wild-type AA genotype. Increased gene expression due to rs7089580 T allele leads to an increased rate of warfarin metabolism and increased warfarin dose requirements. In a study published in 2014, the AT genotype showed slightly higher expression than TT, but both much higher than AA.[36]Another variant, rs1934969 (in studies of 2012 and 2014) have been shown to affect the ability to metabolize losartan: carriers of the TT genotype have increased CYP2C9 hydroxylation capacity for losartan comparing to AA genotype, and, as a result, the lower metabolic ratio of losartan, i.e., faster losartan metabolism.[37][38]

Ligands

[edit]

Most inhibitors of CYP2C9 arecompetitive inhibitors.Noncompetitive inhibitorsof CYP2C9 includenifedipine,[39][40]phenethyl isothiocyanate,[41]medroxyprogesterone acetate[42]and6-hydroxyflavone.It was indicated that the noncompetitive binding site of6-hydroxyflavoneis the reported allosteric binding site of the CYP2C9 enzyme.[43]

Following is a table of selectedsubstrates,inducersandinhibitorsof CYP2C9. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C9 can be classified by theirpotency,such as:

  • Strongbeing one that causes at least a 5-fold increase in the plasmaAUC values,or more than 80% decrease inclearance.[44]
  • Moderatebeing one that causes at least a 2-fold increase in the plasma AUC values, or a 50–80% decrease in clearance.[44]
  • Weakbeing 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.[44][45]
Selected inducers, inhibitors and substrates of CYP2C9
Substrates Inhibitors Inducers

Strong

Moderate

Weak

Unspecified potency

Strong

Weak

Epoxygenase activity

[edit]

CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e.alkene) bonds to formepoxideproducts that act as signaling molecules. It along with CYP2C8,CYP2C19,CYP2J2,and possiblyCYP2S1are the principle enzymes which metabolizes1)arachidonic acidto variousepoxyeicosatrienoic acids(also termed EETs);2)linoleic acidto 9,10-epoxy-octadecenoic acids (also termedcoronaric acid,linoleic acid 9,10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic acids (also termedvernolic acid,linoleic acid 12,13-oxide, or isoleukotoxin);3)docosahexaenoic acidto variousepoxydocosapentaenoic acids(also termed EDPs); and4)eicosapentaenoic acidto various epoxyeicosatetraenoic acids (also termed EEQs).[9]Animal model studies implicate these epoxides in regulating:hypertension,myocardial infarctionand other insults 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 (seeEpoxyeicosatrienoic acidandEpoxygenase).[9]Since the consumption ofomega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of the EDP and EEQ metabolites of the omega-3 fatty acid, i.e. docosahexaenoic and eicosapentaenoic acids, in animals and humans and in humans is the most prominent change in the profile ofpolyunsaturated fatty acidsmetabolites caused by dietary omega-3 fatty acids,eicosapentaenoic acidsand EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[11][14][15]

See also

[edit]

References

[edit]
  1. ^abcGRCh38: Ensembl release 89: ENSG00000138109–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000067231–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^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): 3247–3255.doi:10.1021/bi00227a012.PMID2009263.
  6. ^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".The Japanese Journal of Human Genetics.39(3): 337–343.doi:10.1007/BF01874052.PMID7841444.
  7. ^abcPublic DomainThis article incorporatespublic domain materialfrom"CYP2C9".National Center for Biotechnology Information, U.S. National Library of Medicine.National Center for Biotechnology Information.29 March 2021.This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by rifampin. The enzyme is known to metabolize many xenobiotics, including phenytoin, tolbutamide, ibuprofen, and S-warfarin. Studies identifying individuals who are poor metabolizers of phenytoin and tolbutamide suggest that this gene is polymorphic. The gene is located within a cluster of cytochrome P450 genes on chromosome 10q24. Public DomainThis article incorporates text from this source, which is in thepublic domain.
  8. ^Rettie AE, Jones JP (2005). "Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics".Annual Review of Pharmacology and Toxicology.45:477–494.doi:10.1146/annurev.pharmtox.45.120403.095821.PMID15822186.
  9. ^abcdeSpector AA, Kim HY (April 2015)."Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism".Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.1851(4): 356–365.doi:10.1016/j.bbalip.2014.07.020.PMC4314516.PMID25093613.
  10. ^Westphal C, Konkel A, Schunck WH (November 2011). "CYP-eicosanoids – a new link between omega-3 fatty acids and cardiac disease?".Prostaglandins & Other Lipid Mediators.96(1–4): 99–108.doi:10.1016/j.prostaglandins.2011.09.001.PMID21945326.
  11. ^abcFleming I (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease".Pharmacological Reviews.66(4): 1106–1140.doi:10.1124/pr.113.007781.PMID25244930.S2CID39465144.
  12. ^Zhang G, Kodani S, Hammock BD (January 2014)."Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer".Progress in Lipid Research.53:108–123.doi:10.1016/j.plipres.2013.11.003.PMC3914417.PMID24345640.
  13. ^He J, Wang C, Zhu Y, Ai D (May 2016)."Soluble epoxide hydrolase: A potential target for metabolic diseases".Journal of Diabetes.8(3): 305–313.doi:10.1111/1753-0407.12358.PMID26621325.
  14. ^abcWagner K, Vito S, Inceoglu B, Hammock BD (October 2014)."The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling".Prostaglandins & Other Lipid Mediators.113–115: 2–12.doi:10.1016/j.prostaglandins.2014.09.001.PMC4254344.PMID25240260.
  15. ^abFischer 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 (June 2014)."Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway".Journal of Lipid Research.55(6): 1150–1164.doi:10.1194/jlr.M047357.PMC4031946.PMID24634501.
  16. ^abcdefPratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE (September 2019)."Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists".The Journal of Molecular Diagnostics.21(5): 746–755.doi:10.1016/j.jmoldx.2019.04.003.PMC7057225.PMID31075510.
  17. ^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.doi:10.1007/BF03256440.PMID16646575.S2CID25261882.
  18. ^Rosemary J, Adithan C (January 2007). "The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance".Current Clinical Pharmacology.2(1): 93–109.doi:10.2174/157488407779422302.PMID18690857.
  19. ^"PharmGKB".PharmGKB.Archivedfrom the original on 3 October 2022.Retrieved3 October2022.
  20. ^"CYP2C9 CPIC guidelines".cpicpgx.org.Archivedfrom the original on 3 October 2022.Retrieved3 October2022.
  21. ^ab"PharmVar".www.pharmvar.org.Archivedfrom the original on 17 July 2020.Retrieved14 July2020.
  22. ^Botton MR, Lu X, Zhao G, Repnikova E, Seki Y, Gaedigk A, Schadt EE, Edelmann L, Scott SA (November 2019)."Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles".Human Mutation.40(11): e37–e51.doi:10.1002/humu.23855.PMC6810756.PMID31260137.
  23. ^Botton, Whirl-Carrillo, Tredici, Sangkuhl, Cavallari, Agúndez, Duconge J, Lee, Woodahl, Claudio-Campos, Daly, Klein, Pratt, Scott, Gaedigk (June 2020)."PharmVar GeneFocus: CYP2C19".Clinical Pharmacology and Therapeutics.109(2): 352–366.doi:10.1002/cpt.1973.PMC7769975.PMID32602114.
  24. ^Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (August 1996). "The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism".Pharmacogenetics.6(4): 341–349.doi:10.1097/00008571-199608000-00007.PMID8873220.
  25. ^Tornio A, Backman JT (2018). "Cytochrome P450 in Pharmacogenetics: An Update".Pharmacogenetics.Advances in Pharmacology (San Diego, Calif.). Vol. 83. Academic Press. pp. 3–32.doi:10.1016/bs.apha.2018.04.007.hdl:10138/300396.ISBN9780128133811.PMID29801580.
  26. ^Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT (November 2014)."Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing".Clinical Pharmacology and Therapeutics.96(5): 542–548.doi:10.1038/clpt.2014.159.PMC4206662.PMID25099164.
  27. ^Sychev DA, Shuev GN, Suleymanov SS, Ryzhikova KA, Mirzaev KB, Grishina EA, Snalina NE, Sozaeva ZA, Grabuzdov AM, Matsneva IA (2017)."SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations".Pharmacogenomics and Personalized Medicine.10:93–99.doi:10.2147/PGPM.S129665.PMC5386602.PMID28435307.
  28. ^Topić E, Stefanović M, Samardzija M (January 2004). "Association between the CYP2C9 polymorphism and the drug metabolism phenotype".Clinical Chemistry and Laboratory Medicine.42(1): 72–78.doi:10.1515/CCLM.2004.014.PMID15061384.S2CID22090671.
  29. ^"CYP2C9 allele nomenclature".Archivedfrom the original on 13 January 2010.Retrieved5 March2010.
  30. ^Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA, The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism, Pharmacogenetics. 1996 Aug; 6(4):341–349
  31. ^abSaikatikorn Y, Lertkiatmongkol P, Assawamakin A, Ruengjitchatchawalya M, Tongsima S (November 2010)."Study of the Structural Pathology Caused by CYP2C9 Polymorphisms towards Flurbiprofen Metabolism Using Molecular Dynamics Simulation.".In Chan JH, Ong YS, Cho SB (eds.).International Conference on Computational Systems – Biology and Bioinformatics.Communications in Computer and Information Science. Vol. 115. Berlin, Heidelberg: Springer. pp. 26–35.doi:10.1007/978-3-642-16750-8_3.ISBN978-3-642-16749-2.Archivedfrom the original on 24 February 2024.Retrieved24 January2022.
  32. ^"rs72558187 allele frequency".National Center for Biotechnology Information.Archivedfrom the original on 20 October 2020.Retrieved20 November2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  33. ^Claudio-Campos K, Labastida A, Ramos A, Gaedigk A, Renta-Torres J, Padilla D, Rivera-Miranda G, Scott SA, Ruaño G, Cadilla CL, Duconge-Soler J (2017)."Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study".Frontiers in Pharmacology.8:347.doi:10.3389/fphar.2017.00347.PMC5461284.PMID28638342.
  34. ^Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, Soranzo N, Whittaker P, Ranganath V, Kumanduri V, McLaren W, Holm L, Lindh J, Rane A, Wadelius M, Deloukas P (March 2009)."A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose".PLOS Genetics.5(3): e1000433.doi:10.1371/journal.pgen.1000433.PMC2652833.PMID19300499.
  35. ^"PharmGKB".PharmGKB.Archivedfrom the original on 8 September 2015.Retrieved30 August2020.
  36. ^Hernandez W, Aquino-Michaels K, Drozda K, Patel S, Jeong Y, Takahashi H, Cavallari LH, Perera MA (June 2015)."Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans".Translational Research.165(6): 651–657.doi:10.1016/j.trsl.2014.11.006.PMC4433569.PMID25499099.
  37. ^Dorado P, Gallego A, Peñas-LLedó E, Terán E, LLerena A (August 2014). "Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers".Pharmacogenomics.15(11): 1417–1421.doi:10.2217/pgs.14.85.PMID25303293.
  38. ^Hatta FH, Teh LK, Helldén A, Hellgren KE, Roh HK, Salleh MZ, Aklillu E, Bertilsson L (July 2012). "Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes".European Journal of Clinical Pharmacology.68(7): 1033–1042.doi:10.1007/s00228-012-1210-0.PMID22294058.S2CID8779233.
  39. ^Bourrié M, Meunier V, Berger Y, Fabre G (February 1999). "Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes".Drug Metabolism and Disposition.27(2): 288–296.PMID9929518.
  40. ^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".Cellular and Molecular Neurobiology.24(1): 63–76.doi:10.1023/B:CEMN.0000012725.31108.4a.PMID15049511.S2CID22669449.
  41. ^Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T (August 2001). "Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate".Drug Metabolism and Disposition.29(8): 1110–1113.PMID11454729.
  42. ^Zhang JW, Liu Y, Li W, Hao DC, Yang L (July 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.PMID16645869.S2CID22333299.
  43. ^abcdeSi 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 Metabolism and Disposition.37(3): 629–634.doi:10.1124/dmd.108.023416.PMID19074529.S2CID285706.
  44. ^abcdefghijklmnopqrstuvwxyzaaabacadaeafagahaiajakalamanaoapaqarasatauavFlockhart DA (2007)."Drug Interactions: Cytochrome P450 Drug Interaction Table".Indiana University School of Medicine.Archivedfrom the original on 10 October 2007.Retrieved10 July2011.
  45. ^abcde"Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers".U.S. Food and Drug Administration.Archivedfrom the original on 23 April 2019.Retrieved13 March2016.
  46. ^abcdSousa MC, Braga RC, Cintra BA, de Oliveira V, Andrade CH (2013)."In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9".Food Research International.50:102–110.doi:10.1016/j.foodres.2012.09.027.
  47. ^abcdefghijklmnopqrstFASS (drug formulary):"Facts for prescribers (Fakta för förskrivare)".Swedish environmental classification of pharmaceuticals(in Swedish).Archivedfrom the original on 11 June 2002.Retrieved5 March2010.
  48. ^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 Metabolism and Disposition.33(6): 749–753.doi:10.1124/dmd.105.003616.PMID15764711.S2CID24199800.
  49. ^"ketoprofen | C16H14O3".PubChem.Archivedfrom the original on 1 April 2016.Retrieved30 March2016.
  50. ^Abdullah Alkattan & Eman Alsalameen (2021) Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment, Expert Opinion on Drug Metabolism & Toxicology,doi:10.1080/17425255.2021.1925249
  51. ^Bland TM, Haining RL, Tracy TS, Callery PS (October 2005). "CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin".Biochemical Pharmacology.70(7): 1096–1103.doi:10.1016/j.bcp.2005.07.007.PMID16112652.
  52. ^Patton AL, Seely KA, Yarbrough AL, Fantegrossi W, James LP, McCain KR, Fujiwara R, Prather PL, Moran JH, Radominska-Pandya A (April 2018)."Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants".Biochemical and Biophysical Research Communications.498(3): 597–602.doi:10.1016/j.bbrc.2018.03.028.PMC6425723.PMID29522717.
  53. ^Stout SM, Cimino NM (February 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.PMID24160757.S2CID29133059.Archivedfrom the original on 6 October 2022.Retrieved7 December2017.
  54. ^Miyazawa M, Shindo M, Shimada T (May 2002). "Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes".Drug Metabolism and Disposition.30(5): 602–607.doi:10.1124/dmd.30.5.602.PMID11950794.S2CID2120209.
  55. ^Kosuge K, Jun Y, Watanabe H, Kimura M, Nishimoto M, Ishizaki T, Ohashi K (October 2001). "Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status".Drug Metabolism and Disposition.29(10): 1284–1289.PMID11560871.
  56. ^Lutz JD, VandenBrink BM, Babu KN, Nelson WL, Kunze KL, Isoherranen N (December 2013)."Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems".Drug Metabolism and Disposition.41(12). American Society for Pharmacology & Experimental Therapeutics (ASPET): 2056–2065.doi:10.1124/dmd.113.052639.PMC3834134.PMID23785064.
  57. ^"Verapamil: Drug information. Lexicomp".UpToDate.Archivedfrom the original on 13 January 2019.Retrieved13 January2019.
  58. ^"Candesartan Tablet".DailyMed.27 June 2017.Archivedfrom the original on 7 February 2019.Retrieved6 February2019.
  59. ^"Edarbi – azilsartan kamedoxomil tablet".DailyMed.25 January 2018.Archivedfrom the original on 7 February 2019.Retrieved6 February2019.
  60. ^Kimura Y, Ito H, Ohnishi R, Hatano T (January 2010). "Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity".Food and Chemical Toxicology.48(1): 429–435.doi:10.1016/j.fct.2009.10.041.PMID19883715.
  61. ^Pan X, Tan N, Zeng G, Zhang Y, Jia R (October 2005). "Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B".Bioorganic & Medicinal Chemistry.13(20): 5819–5825.doi:10.1016/j.bmc.2005.05.071.PMID16084098.
  62. ^"Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers".FDA.26 May 2021.Archivedfrom the original on 4 November 2020.Retrieved21 June2020.
  63. ^Kudo T, Endo Y, Taguchi R, Yatsu M, Ito K (May 2015). "Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes".Xenobiotica; the Fate of Foreign Compounds in Biological Systems.45(5): 413–419.doi:10.3109/00498254.2014.990948.PMID25470432.S2CID26910995.
  64. ^Tirkkonen T, Heikkilä P, Huupponen R, Laine K (October 2010). "Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide".Journal of Internal Medicine.268(4): 359–366.doi:10.1111/j.1365-2796.2010.02257.x.PMID20698928.S2CID45449460.
  65. ^abHe 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".European Journal of Clinical Pharmacology.57(12): 847–851.doi:10.1007/s00228-001-0399-0.PMID11936702.S2CID601644.
  66. ^Phucharoenrak P, Trachootham D (February 2024)."Bergaptol, a Major Furocoumarin in Citrus: Pharmacological Properties and Toxicity".Molecules.29(3): 713.doi:10.3390/molecules29030713.PMC10856120.PMID38338457.
  67. ^Park JY, Kim KA, Kim SL (November 2003)."Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes".Antimicrobial Agents and Chemotherapy.47(11): 3464–3469.doi:10.1128/AAC.47.11.3464-3469.2003.PMC253795.PMID14576103.
  68. ^Robertson P, DeCory HH, Madan A, Parkinson A (June 2000). "In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil".Drug Metabolism and Disposition.28(6): 664–671.PMID10820139.
  69. ^Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K (1 January 2012). "Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity".Drug Metabolism and Pharmacokinetics.27(3): 294–300.doi:10.2133/dmpk.DMPK-11-RG-107.PMID22166891.S2CID25863186.
  70. ^Briguglio M, Hrelia S, Malaguti M, Serpe L, Canaparo R, Dell'Osso B, Galentino R, De Michele S, Dina CZ, Porta M, Banfi G (December 2018)."Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles".Pharmaceutics.10(4): 277.doi:10.3390/pharmaceutics10040277.PMC6321138.PMID30558213.
  71. ^Huang TY, Yu CP, Hsieh YW, Lin SP, Hou YC (September 2020)."Resveratrol stereoselectively affected (±)warfarin pharmacokinetics and enhanced the anticoagulation effect".Scientific Reports.10(1): 15910.Bibcode:2020NatSR..1015910H.doi:10.1038/s41598-020-72694-0.PMC7522226.PMID32985569.

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