View source for CYP2C9

{{Short description|Enzyme protein}}
{{Use dmy dates|date=December 2023}}
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{{Use American English|date=February 2024}}
{{Infobox gene}}
'''Cytochrome P450 family 2 subfamily C member 9''' (abbreviated '''CYP2C9''') is an [[enzyme]] [[protein]]. 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 the ''CYP2C9'' [[gene]].<ref name="pmid2009263">{{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 = 3247–3255 | date = April 1991 | pmid = 2009263 | doi = 10.1021/bi00227a012 }}</ref><ref name="pmid7841444">{{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 = 337–343 | date = September 1994 | pmid = 7841444 | doi = 10.1007/BF01874052 | doi-access = free }}</ref> The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.<ref name="ncbi1559">{{NCBI RefSeq|url=https://www.ncbi.nlm.nih.gov/gene/1559| title= CYP2C9 | work = National Center for Biotechnology Information, U.S. National Library of Medicine | date=29 March 2021 | quote=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.}}{{PD-notice}}</ref>

== Function ==
CYP2C9 is a crucial [[cytochrome P450]] enzyme, which plays a significant role in the metabolism, by oxidation, of both xenobiotic and endogenous compounds.<ref name="ncbi1559"/> CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. The protein is mainly expressed in the [[liver]], [[duodenum]], and [[small intestine]].<ref name="ncbi1559"/> About 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 drug]]s. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its [[epoxygenase]] activity, various [[polyunsaturated fatty acid]]s, converting these fatty acids to a wide range of biologically active products.<ref name="pmid15822186">{{cite journal|vauthors=Rettie AE, Jones JP |title=Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics |journal=Annual Review of Pharmacology and Toxicology |volume=45 |pages=477–494 |year=2005 |pmid=15822186 |doi=10.1146/annurev.pharmtox.45.120403.095821}}</ref><ref name="pmid25093613"/>

In particular, CYP2C9 metabolizes [[arachidonic acid]] to the following [[eicosatrienoic acid epoxide]] (EETs) [[stereoisomer]] sets: 5''R'',6''S''-epoxy-8Z,11Z,14Z-eicosatetraenoic and 5''S'',6''R''-epoxy-8Z,11Z,14Z-eicosatetraenoic acids; 11''R'',12''S''-epoxy-8Z,11Z,14Z-eicosatetraenoic and 11''S'',12''R''-epoxy-5Z,8Z,14Z-eicosatetraenoic acids; and 14''R'',15''S''-epoxy-5Z,8Z,11Z-eicosatetraenoic and 14''S'',15''R''-epoxy-5Z,8Z,11Z-eicosatetraenoic acids. It likewise metabolizes [[docosahexaenoic acid]] to [[epoxydocosapentaenoic acid]]s (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) and [[eicosapentaenoic acid]] to [[epoxyeicosatetraenoic acid]]s (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers).<ref>{{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=November 2011 |pmid=21945326 |doi=10.1016/j.prostaglandins.2011.09.001|doi-access=free }}</ref> Animal models and a limited number of human studies implicate these epoxides in reducing [[hypertension]]; protecting against [[myocardial infarction]] and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting [[inflammation]]; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating [[neurohormone]] release and blocking pain perception (see [[epoxyeicosatrienoic acid]] and [[epoxygenase]]).<ref name="pmid25093613"/>

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]], and [[CYP4F3B]]) viz., [[20-Hydroxyeicosatetraenoic acid]] (20-HETE), principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see [[20-Hydroxyeicosatetraenoic acid]], [[epoxyeicosatetraenoic acid]], and [[epoxydocosapentaenoic acid]] sections on activities and clinical significance). Such studies also indicate that the [[eicosapentaenoic acid]]s and 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; and '''3)''' act oppositely from the EETs in that they inhibit [[angiogenesis]], 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.<ref name="pmid25244930">{{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 = 1106–1140 | date = October 2014 | pmid = 25244930 | doi = 10.1124/pr.113.007781 | s2cid = 39465144 | doi-access =  }}</ref><ref>{{cite journal | vauthors = Zhang G, Kodani S, Hammock BD | title = Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer | journal = Progress in Lipid Research | volume = 53 | pages = 108–123 | date = January 2014 | pmid = 24345640 | pmc = 3914417 | doi = 10.1016/j.plipres.2013.11.003 }}</ref><ref>{{cite journal | vauthors = He J, Wang C, Zhu Y, Ai D | title = Soluble epoxide hydrolase: A potential target for metabolic diseases | journal = Journal of Diabetes | volume = 8 | issue = 3 | pages = 305–313 | date = May 2016 | pmid = 26621325 | doi = 10.1111/1753-0407.12358 | doi-access = free }}</ref><ref name="pmid25240260">{{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 | pmc = 4254344 | doi = 10.1016/j.prostaglandins.2014.09.001 }}</ref> 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 of [[polyunsaturated fatty acid]]s metabolites caused by dietary omega-3 fatty acids.<ref name="pmid25244930"/><ref name="pmid25240260"/><ref name="pmid24634501">{{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 = June 2014 | pmid = 24634501 | pmc = 4031946 | doi = 10.1194/jlr.M047357  |doi-access=free }}</ref>

CYP2C9 may also metabolize [[linoleic acid]] to the potentially very toxic products, [[coronaric acid]] (also termed leukotoxin) and [[vernolic acid]] (also termed isoleukotoxin); these linoleic acid epoxides cause [[multiple organ failure]] and [[acute respiratory distress]] in animal models and may contribute to these syndromes in humans.<ref name="pmid25093613"/>

== Pharmacogenomics ==
The ''CYP2C9'' gene is highly polymorphic.<ref name="pmid31075510"/> At least 20 [[single nucleotide polymorphisms]] (SNPs) have been reported to have functional evidence of altered enzyme activity.<ref name="pmid31075510">{{cite journal | vauthors = Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE | title = Recommendations for Clinical CYP2C9 Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists | journal = The Journal of Molecular Diagnostics | volume = 21 | issue = 5 | pages = 746–755 | date = September 2019 | pmid = 31075510 | pmc = 7057225 | doi = 10.1016/j.jmoldx.2019.04.003 }}</ref> 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.<ref name="pmid16646575">{{cite journal | vauthors = García-Martín E, Martínez C, Ladero JM, Agúndez JA | s2cid = 25261882 | 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 = 2006 | pmid = 16646575 | doi = 10.1007/BF03256440 }}</ref><ref name="pmid18690857">{{cite journal | vauthors = Rosemary J, Adithan C | title = The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance | journal = Current Clinical Pharmacology | volume = 2 | issue = 1 | pages = 93–109 | date = Jan 2007 | pmid = 18690857 | doi = 10.2174/157488407779422302 }}</ref> Information about how human genetic variation of CYP2C9 affects response to medications can be found in databases such PharmGKB,<ref>{{cite web |title=PharmGKB |url=https://www.pharmgkb.org/gene/PA126/prescribingInfo |access-date=3 October 2022 |website=PharmGKB |language=en |archive-date=3 October 2022 |archive-url=https://web.archive.org/web/20221003091852/https://www.pharmgkb.org/gene/PA126/prescribingInfo |url-status=live }}</ref> Clinical Pharmacogenetics Implementation Consortium (CPIC).<ref>{{cite web |title=CYP2C9 CPIC guidelines |url=https://cpicpgx.org/gene/cyp2c9/ |access-date=3 October 2022 |website=cpicpgx.org |language=en-US |archive-date=3 October 2022 |archive-url=https://web.archive.org/web/20221003091856/https://cpicpgx.org/gene/cyp2c9/ |url-status=live }}</ref>

The label CYP2C9*1 is assigned by the [[Pharmacogene Variation Consortium]] (PharmVar) to the most commonly observed human gene variant.<ref name="PharmVarDbPage"/> Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label.<ref name="pmid31260137">{{cite journal | vauthors = Botton MR, Lu X, Zhao G, Repnikova E, Seki Y, Gaedigk A, Schadt EE, Edelmann L, Scott SA | title = Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles | journal = Human Mutation | volume = 40 | issue = 11 | pages = e37–e51 | date = November 2019 | pmid = 31260137 | doi = 10.1002/humu.23855 | pmc = 6810756 }}</ref><ref name="pmid32602114">{{cite journal | vauthors = Botton, Whirl-Carrillo, Tredici, Sangkuhl, Cavallari, Agúndez, Duconge J, Lee, Woodahl, Claudio-Campos, Daly, Klein, Pratt, Scott, Gaedigk | title = PharmVar GeneFocus: CYP2C19 | journal = Clinical Pharmacology and Therapeutics | date = June 2020 | volume = 109 | issue = 2 | pages = 352–366 | pmid = 32602114 | doi = 10.1002/cpt.1973 | pmc = 7769975 | doi-access = free }}</ref> 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.&nbsp;Ile359Leu, rs1057910),<ref name="pmid8873220">{{cite journal | vauthors = Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA | title = The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism | journal = Pharmacogenetics | volume = 6 | issue = 4 | pages = 341–349 | date = August 1996 | pmid = 8873220 | doi = 10.1097/00008571-199608000-00007}}</ref> causing reductions in enzyme activity of 30% and 80%, respectively.<ref name="pmid31075510"/>

=== Metabolizer phenotypes ===
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.<ref>{{cite book | vauthors = Tornio A, Backman JT | title = Pharmacogenetics | chapter = Cytochrome P450 in Pharmacogenetics: An Update | volume = 83 | pages = 3–32 | year = 2018 | pmid = 29801580 | doi = 10.1016/bs.apha.2018.04.007 | series = Advances in Pharmacology (San Diego, Calif.) | publisher = Academic Press | hdl = 10138/300396 | isbn = 9780128133811 }}</ref> 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).<ref name="pmid25099164">{{cite journal | vauthors = Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT | title = Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing | journal = Clinical Pharmacology and Therapeutics | volume = 96 | issue = 5 | pages = 542–548 | date = November 2014 | pmid = 25099164 | pmc = 4206662 | doi = 10.1038/clpt.2014.159 | author9 = Clinical Pharmacogenetics Implementation Consortium }}</ref><ref>{{cite journal | vauthors = Sychev DA, Shuev GN, Suleymanov SS, Ryzhikova KA, Mirzaev KB, Grishina EA, Snalina NE, Sozaeva ZA, Grabuzdov AM, Matsneva IA | title = SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations | journal = Pharmacogenomics and Personalized Medicine | volume = 10 | pages = 93–99 | year = 2017 | pmid = 28435307 | pmc = 5386602 | doi = 10.2147/PGPM.S129665 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Topić E, Stefanović M, Samardzija M | title = Association between the CYP2C9 polymorphism and the drug metabolism phenotype | journal = Clinical Chemistry and Laboratory Medicine | volume = 42 | issue = 1 | pages = 72–78 | date = January 2004 | pmid = 15061384 | doi = 10.1515/CCLM.2004.014 | s2cid = 22090671 }}</ref>

CYP2C9*3 reflects an [[Isoleucine|Ile]]359-[[Leucine|Leu]] (I359L) change in the [[amino acid]] sequence,<ref name="CYP2C9">{{Cite web |url=http://www.cypalleles.ki.se/cyp2c9.htm |title=CYP2C9 allele nomenclature |access-date=5 March 2010 |archive-date=13 January 2010 |archive-url=https://web.archive.org/web/20100113045258/http://www.cypalleles.ki.se/cyp2c9.htm |url-status=live }}</ref> and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin.<ref name="pmid8873220"/> Its prevalence varies with race as:

{| class="wikitable"
|-
! colspan="6"| 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 ===
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.<ref name="pmid31075510"/>

CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p.&nbsp;Leu90Pro, rs72558187).<ref name="pmid31075510"/> CYP2C9*13 prevalence is approximately 1% in the Asian population,<ref name="Saikatikorn-2010">{{cite book | vauthors = Saikatikorn Y, Lertkiatmongkol P, Assawamakin A, Ruengjitchatchawalya M, Tongsima S | chapter = Study of the Structural Pathology Caused by CYP2C9 Polymorphisms towards Flurbiprofen Metabolism Using Molecular Dynamics Simulation. | veditors = Chan JH, Ong YS, Cho SB | title = International Conference on Computational Systems – Biology and Bioinformatics | series = Communications in Computer and Information Science | date = November 2010 | volume = 115 | pages = 26–35 | publisher = Springer | location = Berlin, Heidelberg | doi = 10.1007/978-3-642-16750-8_3 | isbn = 978-3-642-16749-2 | chapter-url = https://books.google.com/books?id=oHmqCAAAQBAJ&pg=PA27 | access-date = 24 January 2022 | archive-date = 24 February 2024 | archive-url = https://web.archive.org/web/20240224233906/https://books.google.com/books?id=oHmqCAAAQBAJ&pg=PA27#v=onepage&q&f=false | url-status = live }}</ref> but in Caucasians this variant prevalence is almost zero.<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/snp/rs72558187#frequency_tab |title=rs72558187 allele frequency |publisher=National Center for Biotechnology Information |access-date=20 November 2020 |archive-date=20 October 2020 |archive-url=https://web.archive.org/web/20201020115858/https://www.ncbi.nlm.nih.gov/snp/rs72558187#frequency_tab |url-status=live }}{{PD-notice}}</ref> 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 as [[diclofenac]] and [[flurbiprofen]].<ref name="Saikatikorn-2010" /> 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.<ref name="pmid31075510"/> {{as of|2020|lc=n}} the evidence level for CYP2C9*13 in the [[Pharmacogene Variation Consortium|PharmVar]] database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive.<ref name="PharmVarDbPage">{{cite web|url=https://www.pharmvar.org/gene/CYP2C9|title=PharmVar|website=www.pharmvar.org|access-date=14 July 2020|archive-date=17 July 2020|archive-url=https://web.archive.org/web/20200717040510/https://www.pharmvar.org/gene/CYP2C9|url-status=live}}</ref>

=== Additional variants ===
Not all clinically significant genetic variant alleles have been registered by [[Pharmacogene Variation Consortium|PharmVar]]. For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4&nbsp;mg/day) than common variants CYP2C9*2 and CYP2C9*3.<ref>{{cite journal | vauthors = 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 | title = Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study | journal = Frontiers in Pharmacology | volume = 8 | pages = 347 | year = 2017 | pmid = 28638342 | pmc = 5461284 | doi = 10.3389/fphar.2017.00347 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose | journal = PLOS Genetics | volume = 5 | issue = 3 | pages = e1000433 | date = March 2009 | pmid = 19300499 | pmc = 2652833 | doi = 10.1371/journal.pgen.1000433 | doi-access = free }}</ref> 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.<ref>{{cite web|url=https://www.pharmgkb.org/clinicalAnnotation/1043880397|title=PharmGKB|website=PharmGKB|access-date=30 August 2020|archive-date=8 September 2015|archive-url=https://web.archive.org/web/20150908175904/https://www.pharmgkb.org/clinicalAnnotation/1043880397|url-status=live}}</ref> 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.<ref>{{cite journal | vauthors = Hernandez W, Aquino-Michaels K, Drozda K, Patel S, Jeong Y, Takahashi H, Cavallari LH, Perera MA | title = Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans | journal = Translational Research | volume = 165 | issue = 6 | pages = 651–657 | date = June 2015 | pmid = 25499099 | pmc = 4433569 | doi = 10.1016/j.trsl.2014.11.006 }}</ref> 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.<ref>{{cite journal | vauthors = Dorado P, Gallego A, Peñas-LLedó E, Terán E, LLerena A | title = Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers | journal = Pharmacogenomics | volume = 15 | issue = 11 | pages = 1417–1421 | date = August 2014 | pmid = 25303293 | doi = 10.2217/pgs.14.85 }}</ref><ref>{{cite journal | vauthors = Hatta FH, Teh LK, Helldén A, Hellgren KE, Roh HK, Salleh MZ, Aklillu E, Bertilsson L | title = Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes | journal = European Journal of Clinical Pharmacology | volume = 68 | issue = 7 | pages = 1033–1042 | date = July 2012 | pmid = 22294058 | doi = 10.1007/s00228-012-1210-0 | s2cid = 8779233 }}</ref>

==Ligands==

Most inhibitors of CYP2C9 are [[Competitive inhibition|competitive inhibitor]]s. [[Non-competitive inhibition|Noncompetitive inhibitors]] of CYP2C9  include [[nifedipine]],<ref name="pmid9929518">{{cite journal | vauthors = Bourrié M, Meunier V, Berger Y, Fabre G | title = Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes | journal = Drug Metabolism and Disposition | volume = 27 | issue = 2 | pages = 288–296 | date = February 1999 | pmid = 9929518 }}</ref><ref name="pmid15049511">{{cite journal | vauthors = Salsali M, Holt A, Baker GB | s2cid = 22669449 | title = Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6 | journal = Cellular and Molecular Neurobiology | volume = 24 | issue = 1 | pages = 63–76 | date = February 2004 | pmid = 15049511 | doi = 10.1023/B:CEMN.0000012725.31108.4a | pmc = 11529937 }}</ref> [[phenethyl isothiocyanate]],<ref name="pmid11454729">{{cite journal | vauthors = Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T | title = Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate | journal = Drug Metabolism and Disposition | volume = 29 | issue = 8 | pages = 1110–1113 | date = August 2001 | pmid = 11454729 }}</ref> [[medroxyprogesterone acetate]]<ref name="pmid16645869">{{cite journal | vauthors = Zhang JW, Liu Y, Li W, Hao DC, Yang L | s2cid = 22333299 | title = Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes | journal = European Journal of Clinical Pharmacology | volume = 62 | issue = 7 | pages = 497–502 | date = July 2006 | pmid = 16645869 | doi = 10.1007/s00228-006-0128-9 }}</ref> and [[6-hydroxyflavone]]. It was indicated that the noncompetitive binding site of [[6-hydroxyflavone]] is the reported allosteric binding site of the CYP2C9 enzyme.<ref name="pmid19074529">{{cite journal | vauthors = Si D, Wang Y, Zhou YH, Guo Y, Wang J, Zhou H, Li ZS, Fawcett JP | s2cid = 285706 | title = Mechanism of CYP2C9 inhibition by flavones and flavonols | journal = Drug Metabolism and Disposition | volume = 37 | issue = 3 | pages = 629–634 | date = March 2009 | pmid = 19074529 | doi = 10.1124/dmd.108.023416 }}</ref>

Following is a table of selected [[enzyme substrate|substrates]], [[enzyme induction and inhibition|inducers]] and [[enzyme induction and inhibition|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 (pharmacology)|potency]], such as:
* '''Strong''' being one that causes at least a 5-fold increase in the plasma [[area under the curve (pharmacokinetics)|AUC values]], or more than 80% decrease in [[clearance (medicine)|clearance]].<ref name="Flockhart-2007"/>
* '''Moderate''' being one that causes at least a 2-fold increase in the plasma AUC values, or a 50–80% decrease in clearance.<ref name="Flockhart-2007"/>
* '''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.<ref name="Flockhart-2007">{{cite web |vauthors=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 |access-date=10 July 2011 |archive-date=10 October 2007 |archive-url=https://web.archive.org/web/20071010053126/http://medicine.iupui.edu/flockhart/table.htm |url-status=live }}</ref><ref name="usfda-tsii">{{cite web|title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm|website=U.S. Food and Drug Administration|access-date=13 March 2016|archive-date=23 April 2019|archive-url=https://web.archive.org/web/20190423033345/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm|url-status=dead}}</ref>

{| class="wikitable"
|+'''Selected inducers, inhibitors and substrates of CYP2C9'''
|-
! Substrates !! Inhibitors !! Inducers
|- style="vertical-align: top;"
|
* dietary [[flavonoid]]s
** [[naringenin]]<ref name="Sousa-2013">{{cite journal |title=In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9|year=2013|doi=10.1016/j.foodres.2012.09.027| vauthors = Sousa MC, Braga RC, Cintra BA, de Oliveira V, Andrade CH |journal=Food Research International|volume=50|pages=102–110|doi-access=free}}</ref>
** [[naringin]]<ref name="Sousa-2013" />
** [[quercetin]]<ref name="Sousa-2013" />
** [[rutin]]<ref name="Sousa-2013" />
* [[NSAID]]s ([[analgesic]], [[antipyretic]], [[anti-inflammatory]])
** [[celecoxib]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[lornoxicam]]<ref name="Flockhart-2007"/><ref name="pmid15764711">{{cite journal | vauthors = Guo Y, Zhang Y, Wang Y, Chen X, Si D, Zhong D, Fawcett JP, Zhou H | s2cid = 24199800 | title = Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in humans | journal = Drug Metabolism and Disposition | volume = 33 | issue = 6 | pages = 749–753 | date = June 2005 | pmid = 15764711 | doi = 10.1124/dmd.105.003616 }}</ref>
** [[diclofenac]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[ibuprofen]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[naproxen]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[ketoprofen]]<ref name="Ketoprofen, PubChem">{{cite web | url = https://pubchem.ncbi.nlm.nih.gov/compound/3825#x301 | title = ketoprofen &#124; C16H14O3 | work = PubChem | access-date = 30 March 2016 | archive-date = 1 April 2016 | archive-url = https://web.archive.org/web/20160401190233/http://pubchem.ncbi.nlm.nih.gov/compound/3825/#x301 | url-status = live }}</ref>
** [[piroxicam]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[meloxicam]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[suprofen]]<ref name="Flockhart-2007"/>
* [[phenytoin]]<ref name="Flockhart-2007"/><ref name="FASS"/> ([[antiepileptic]])
* [[2-oxo-clopidogrel]] (an inactive metabolite of clopidogrel prodrug)<ref>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}}
</ref>
* [[fluvastatin]]<ref name="Flockhart-2007"/><ref name="FASS"/> ([[statin]])
* [[sulfonylurea]]s ([[antidiabetic]])
** [[glipizide]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[glibenclamide]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[glimepiride]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[tolbutamide]]<ref name="Flockhart-2007"/>
** [[glyburide]]<ref name="Flockhart-2007"/>
* [[angiotensin II receptor antagonists]] (in [[hypertension]], [[diabetic nephropathy]], [[congestive heart failure|CHF]])
** [[irbesartan]]<ref name="Flockhart-2007"/><ref name="FASS"/>
** [[losartan]] ([[sensitive substrate]])<ref name="Flockhart-2007"/><ref name="FASS"/>
* [[S-warfarin]]<ref name="Flockhart-2007"/><ref name="FASS"/> ([[anticoagulant]])
* [[sildenafil]]<ref name="FASS"/> (in [[erectile dysfunction]])
* [[terbinafine]]<ref name="FASS"/> ([[Antifungal medication|antifungal]])
* [[amitriptyline]]<ref name="Flockhart-2007"/> ([[tricyclic antidepressant]])
* [[fluoxetine]]<ref name="Flockhart-2007"/> ([[selective serotonin reuptake inhibitor|SSRI]] antidepressant)
* [[nateglinide]]<ref name="Flockhart-2007"/> (antidiabetic)
* [[rosiglitazone]]<ref name="Flockhart-2007"/> ([[antidiabetic]])
* [[tamoxifen]]<ref name="Flockhart-2007"/> ([[selective estrogen receptor modulator|SERM]])
* [[torasemide]]<ref name="Flockhart-2007"/> ([[loop diuretic]])
* [[tetrahydrocannabinol|THC]]<ref name="pmid16112652">{{cite journal | vauthors = Bland TM, Haining RL, Tracy TS, Callery PS | title = CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin | journal = Biochemical Pharmacology | volume = 70 | issue = 7 | pages = 1096–1103 | date = October 2005 | pmid = 16112652 | doi = 10.1016/j.bcp.2005.07.007 }}</ref>
* [[JWH-018]]<ref name="pmid29522717">{{cite journal | vauthors = Patton AL, Seely KA, Yarbrough AL, Fantegrossi W, James LP, McCain KR, Fujiwara R, Prather PL, Moran JH, Radominska-Pandya A | title = Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants | journal = Biochemical and Biophysical Research Communications | volume = 498 | issue = 3 | pages = 597–602 | date = April 2018 | pmid = 29522717 | pmc = 6425723 | doi = 10.1016/j.bbrc.2018.03.028 }}</ref>
* [[AM-2201]]<ref>{{cite journal | vauthors = Stout SM, Cimino NM | s2cid = 29133059 | title = Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review | journal = Drug Metabolism Reviews | volume = 46 | issue = 1 | pages = 86–95 | date = February 2014 | pmid = 24160757 | doi = 10.3109/03602532.2013.849268 | url = https://zenodo.org/record/1093138 | access-date = 7 December 2017 | archive-date = 6 October 2022 | archive-url = https://web.archive.org/web/20221006071438/https://zenodo.org/record/1093138 | url-status = live }}</ref>
* [[limonene]]<ref>{{cite journal | vauthors = Miyazawa M, Shindo M, Shimada T | title = Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes | journal = Drug Metabolism and Disposition | volume = 30 | issue = 5 | pages = 602–607 | date = May 2002 | pmid = 11950794 | doi=10.1124/dmd.30.5.602| s2cid = 2120209 }}</ref> ([[monoterpene]])
* [[tapentadol]] ([[analgesic]])
* [[polyunsaturated fatty acids]]
* [[montelukast]] ([[leukotriene receptor antagonist]])
* [[diltiazem]] (minor/[[moderate sensitive substrates]]) <ref name="pmid11560871">{{cite journal | vauthors = Kosuge K, Jun Y, Watanabe H, Kimura M, Nishimoto M, Ishizaki T, Ohashi K | title = Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status | journal = Drug Metabolism and Disposition | volume = 29 | issue = 10 | pages = 1284–1289 | date = October 2001 | pmid = 11560871 }}</ref><ref name="pmid23785064">{{cite journal | vauthors = Lutz JD, VandenBrink BM, Babu KN, Nelson WL, Kunze KL, Isoherranen N | title = Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems | journal = Drug Metabolism and Disposition | volume = 41 | issue = 12 | pages = 2056–2065 | date = December 2013 | pmid = 23785064 | pmc = 3834134 | doi = 10.1124/dmd.113.052639 | publisher = American Society for Pharmacology & Experimental Therapeutics (ASPET) }}</ref>
* [[verapamil]] (minor/[[moderate sensitive substrates]])<ref name="UpToDate">{{cite web | title=Verapamil: Drug information. Lexicomp | website=UpToDate | url=https://www.uptodate.com/contents/verapamil-drug-information | access-date=13 January 2019 | archive-date=13 January 2019 | archive-url=https://web.archive.org/web/20190113232158/https://www.uptodate.com/contents/verapamil-drug-information | url-status=live }}</ref>
* [[candesartan]] ([[Moderate sensitive substrate]])<ref name="CANDESARTAN 2017">{{cite web | title=Candesartan Tablet | website=DailyMed | date=27 June 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ceb5658-b03c-475d-9ef0-2cd0645191d3 | access-date=6 February 2019 | archive-date=7 February 2019 | archive-url=https://web.archive.org/web/20190207020450/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ceb5658-b03c-475d-9ef0-2cd0645191d3 | url-status=live }}</ref>
* [[azilsartan]] (Minor substrate of CYP2C9)<ref name="EDARBI 2018">{{cite web | title=Edarbi – azilsartan kamedoxomil tablet | website=DailyMed | date=25 January 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52b27c75-9f5a-4816-bafd-dace9d7d2063 | access-date=6 February 2019 | archive-date=7 February 2019 | archive-url=https://web.archive.org/web/20190207020429/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52b27c75-9f5a-4816-bafd-dace9d7d2063 | url-status=live }}</ref>
||

'''Strong'''<!--Inhibitors-->
* [[miconazole]]<ref name="FASS"/> ([[Antifungal medication|antifungal]])
* [[amentoflavone]]<ref name="pmid19883715">{{cite journal | vauthors = Kimura Y, Ito H, Ohnishi R, Hatano T | title = Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity | journal = Food and Chemical Toxicology | volume = 48 | issue = 1 | pages = 429–435 | date = Jan 2010 | pmid = 19883715 | doi = 10.1016/j.fct.2009.10.041 }}</ref> (constituent of [[Ginkgo biloba]] and [[Hypericum perforatum|St. John's Wort]])<ref name="pmid16084098">{{cite journal | vauthors = Pan X, Tan N, Zeng G, Zhang Y, Jia R | title = Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B | journal = Bioorganic & Medicinal Chemistry | volume = 13 | issue = 20 | pages = 5819–5825 | date = October 2005 | pmid = 16084098 | doi = 10.1016/j.bmc.2005.05.071 }}</ref>
* [[sulfaphenazole]]<ref name="FASS">[[FASS (drug formulary)]]: {{cite web |url=http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 |title=Facts for prescribers (Fakta för förskrivare) |work=Swedish environmental classification of pharmaceuticals |language=sv |access-date=5 March 2010 |archive-date=11 June 2002 |archive-url=https://web.archive.org/web/20020611044953/http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 |url-status=live }}</ref><ref name="Flockhart-2007"/> ([[antibacterial]])
* [[Valproic acid]]<ref name="FASS"/> ([[anticonvulsant]], [[mood-stabilizing]])
* [[Apigenin]]<ref name="pmid19074529"/>

'''Moderate'''<!--inhibitors-->
* [[amiodarone]]<ref name="Flockhart-2007"/> ([[antiarrhythmic]])
* [[fluconazole]]<ref name="FDA_drug_development">{{cite journal|title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|journal=FDA|date=26 May 2021|url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers|access-date=21 June 2020|archive-date=4 November 2020|archive-url=https://web.archive.org/web/20201104173036/https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers|url-status=live}}</ref><ref name="Flockhart-2007"/> ([[Antifungal medication|antifungal]])
* [[metronidazole]]<ref name="Flockhart-2007"/><ref>{{cite journal | vauthors = Kudo T, Endo Y, Taguchi R, Yatsu M, Ito K | title = Metronidazole reduces the expression of cytochrome P450 enzymes in HepaRG cells and cryopreserved human hepatocytes | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 45 | issue = 5 | pages = 413–419 | date = May 2015 | pmid = 25470432 | doi = 10.3109/00498254.2014.990948 | s2cid = 26910995 }}</ref><ref>{{cite journal | vauthors = Tirkkonen T, Heikkilä P, Huupponen R, Laine K | title = Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide | journal = Journal of Internal Medicine | volume = 268 | issue = 4 | pages = 359–366 | date = October 2010 | pmid = 20698928 | doi = 10.1111/j.1365-2796.2010.02257.x | s2cid = 45449460 | doi-access =  }}</ref> ([[antibiotic]] and [[antiprotozoal medication]])
* [[phenylbutazone]]<ref name="Flockhart-2007"/>

'''Weak'''<!--inhibitors-->
* [[ceritinib]]<ref name="Flockhart-2007"/>
* [[quercetin]]<ref name="Flockhart-2007"/><ref name="pmid19074529"/> (a plant-based [[flavonol]])

'''<!--Inhibitors of-->Unspecified potency'''
* [[antihistamine]]s ([[H1-receptor antagonists]])
** [[cyclizine]]<ref name="pmid11936702">{{cite journal | vauthors = He N, Zhang WQ, Shockley D, Edeki T | s2cid = 601644 | title = Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes | journal = European Journal of Clinical Pharmacology | volume = 57 | issue = 12 | pages = 847–851 | date = February 2002 | pmid = 11936702 | doi = 10.1007/s00228-001-0399-0 }}</ref>
** [[promethazine]]<ref name="pmid11936702"/>
* [[bergaptol]]<ref name="pmid38338457">{{cite journal |vauthors=Phucharoenrak P, Trachootham D |title=Bergaptol, a Major Furocoumarin in Citrus: Pharmacological Properties and Toxicity |journal=Molecules |volume=29 |issue=3 |date=February 2024 |page=713 |pmid=38338457 |pmc=10856120 |doi=10.3390/molecules29030713 |doi-access=free }}</ref>
* [[chloramphenicol]]<ref name="pmid14576103">{{cite journal | vauthors = Park JY, Kim KA, Kim SL | title = Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3464–3469 | date = November 2003 | pmid = 14576103 | pmc = 253795 | doi = 10.1128/AAC.47.11.3464-3469.2003 }}</ref>
* [[fenofibrate]]<ref name="Flockhart-2007"/> ([[fibrate]])
* [[flavones]]<ref name="pmid19074529"/>
* [[flavonols]]<ref name="pmid19074529"/>
* [[fluvastatin]]<ref name="Flockhart-2007"/> ([[statin]])
* [[fluvoxamine]]<ref name="Flockhart-2007"/> ([[SSRI]])
* [[isoniazid]]<ref name="Flockhart-2007"/> (in [[tuberculosis]])
* [[lovastatin]]<ref name="Flockhart-2007"/> ([[statin]])
* [[modafinil]]<ref name="pmid10820139">{{cite journal | vauthors = Robertson P, DeCory HH, Madan A, Parkinson A | title = In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil | journal = Drug Metabolism and Disposition | volume = 28 | issue = 6 | pages = 664–671 | date = June 2000 | pmid = 10820139 }}</ref>
* [[phenylbutazone]]<ref name="Flockhart-2007"/> ([[non-steroidal anti-inflammatory drug|NSAID]])
* [[probenecid]]<ref name="Flockhart-2007"/> ([[uricosuric]])
* [[sertraline]]<ref name="Flockhart-2007"/> ([[SSRI]])
* [[sulfamethoxazole]]<ref name="Flockhart-2007"/> ([[antibiotic]])
* [[teniposide]]<ref name="Flockhart-2007"/> ([[chemotherapeutic]])
* [[voriconazole]]<ref name="Flockhart-2007"/> ([[Antifungal medication|antifungal]])
* [[zafirlukast]]<ref name="Flockhart-2007"/> ([[leukotriene antagonist]])
* [[Tetrahydrocannabinol]], [[cannabidiol]], and [[cannabinol]] (cannabis constituents)<ref>{{cite journal | vauthors = Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K | title = Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity | journal = Drug Metabolism and Pharmacokinetics | volume = 27 | issue = 3 | pages = 294–300 | date = 1 January 2012 | pmid = 22166891 | doi = 10.2133/dmpk.DMPK-11-RG-107 | s2cid = 25863186 }}</ref>
* [[sesamin]]<ref name="pmid30558213">{{cite journal | vauthors = Briguglio M, Hrelia S, Malaguti M, Serpe L, Canaparo R, Dell'Osso B, Galentino R, De Michele S, Dina CZ, Porta M, Banfi G | title = Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles | journal = Pharmaceutics | volume = 10 | issue = 4 | pages = 277 | date = December 2018 | pmid = 30558213 | pmc = 6321138 | doi = 10.3390/pharmaceutics10040277 | doi-access = free }}</ref> (a [[lignan]] from [[fagara]] and [[sesame]])
* [[resveratrol]]<ref name="pmid32985569">{{cite journal | vauthors = Huang TY, Yu CP, Hsieh YW, Lin SP, Hou YC | title = Resveratrol stereoselectively affected (±)warfarin pharmacokinetics and enhanced the anticoagulation effect | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 15910 | date = September 2020 | pmid = 32985569 | pmc = 7522226 | doi = 10.1038/s41598-020-72694-0 | bibcode = 2020NatSR..1015910H }}</ref> (a plant-based [[stilbenoid]])
||

'''Strong'''<!--inducers-->
* [[rifampicin]]<ref name="Flockhart-2007"/><ref name="FASS"/> ([[bactericidal]])
* [[secobarbital]]<ref name="Flockhart-2007"/> ([[barbiturate]])
'''Weak'''<!--inducers-->
* [[aprepitant]]<ref name="usfda-tsii" />
* [[bosentan]]<ref name="usfda-tsii" />
* [[phenobarbital]]<ref name="usfda-tsii" />
* [[St Johns Wort]]<ref name="usfda-tsii" />
|-
|}

==Epoxygenase activity==
CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. [[alkene]]) bonds to form [[epoxide]] products that act as signaling molecules. It along with CYP2C8, [[CYP2C19]], [[CYP2J2]], and possibly [[CYP2S1]] are the principle enzymes which metabolizes '''1)''' [[arachidonic acid]] to various [[epoxyeicosatrienoic acid]]s (also termed EETs); '''2)''' [[linoleic acid]] to 9,10-epoxy-octadecenoic acids (also termed [[coronaric acid]], linoleic acid 9,10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic acids (also termed [[vernolic acid]], linoleic acid 12,13-oxide, or isoleukotoxin); '''3)''' [[docosahexaenoic acid]] to various [[epoxydocosapentaenoic acid]]s (also termed EDPs); and '''4)''' [[eicosapentaenoic acid]] to various epoxyeicosatetraenoic acids (also termed EEQs).<ref name="pmid25093613">{{cite journal | vauthors = Spector AA, Kim HY | title = Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 4 | pages = 356–365 | date = April 2015 | pmid = 25093613 | doi = 10.1016/j.bbalip.2014.07.020 | pmc=4314516}}</ref> Animal model studies implicate these epoxides in regulating: [[hypertension]], [[myocardial infarction]] and 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 (see [[Epoxyeicosatrienoic acid]] and [[Epoxygenase]]).<ref name="pmid25093613"/> Since the consumption of [[omega-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 of [[polyunsaturated fatty acid]]s metabolites caused by dietary omega-3 fatty acids, [[eicosapentaenoic acid]]s and EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.<ref name="pmid25244930"/><ref name="pmid25240260"/><ref name="pmid24634501"/>

== References ==
{{reflist|33em}}

== 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 = 285–299 | date = December 1994 | pmid = 7704034 | doi = 10.1097/00008571-199412000-00001 }}
* {{cite journal | vauthors = Miners JO, Birkett DJ | title = Cytochrome P4502C9: an enzyme of major importance in human drug metabolism | journal = British Journal of Clinical Pharmacology | volume = 45 | issue = 6 | pages = 525–538 | date = June 1998 | pmid = 9663807 | pmc = 1873650 | doi = 10.1046/j.1365-2125.1998.00721.x }}
* {{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 = 1129–1165 | date = December 1998 | pmid = 9890157 | doi = 10.1080/004982598238868 }}
* {{cite journal | vauthors = Henderson RF | title = Species differences in the metabolism of olefins: implications for risk assessment | journal = Chemico-Biological Interactions | volume = 135–136 | pages = 53–64 | date = June 2001 | pmid = 11397381 | doi = 10.1016/S0009-2797(01)00170-3 | bibcode = 2001CBI...135...53H }}
* {{cite journal | vauthors = Xie HG, Prasad HC, Kim RB, Stein CM | title = CYP2C9 allelic variants: ethnic distribution and functional significance | journal = Advanced Drug Delivery Reviews | volume = 54 | issue = 10 | pages = 1257–1270 | date = November 2002 | pmid = 12406644 | doi = 10.1016/S0169-409X(02)00076-5 }}
* {{cite journal | vauthors = Palkimas MP, Skinner HM, Gandhi PJ, Gardner AJ | s2cid = 20497247 | title = Polymorphism induced sensitivity to warfarin: a review of the literature | journal = Journal of Thrombosis and Thrombolysis | volume = 15 | issue = 3 | pages = 205–212 | date = June 2003 | pmid = 14739630 | doi = 10.1023/B:THRO.0000011376.12309.af }}
* {{cite journal | vauthors = Daly AK, Aithal GP | title = Genetic regulation of warfarin metabolism and response | journal = Seminars in Vascular Medicine | volume = 03 | issue = 3 | pages = 231–238 | date = August 2003 | pmid = 15199455 | doi = 10.1055/s-2003-44458 | s2cid = 260370436 }}
{{refend}}

==External links==
{{Commons category}}
* [https://www.pharmgkb.org/search/annotatedGene/cyp2c9/index.jsp PharmGKB: Annotated PGx Gene Information for CYP2C9]
* [http://bioinformatics.charite.de/supercyp/ SuperCYP: Database for Drug-Cytochrome-Interactions] {{Webarchive|url=https://web.archive.org/web/20111103123642/http://bioinformatics.charite.de/supercyp/ |date=3 November 2011 }}
* [https://www.pharmvar.org/gene/CYP2C9 PharmVar Database for CYP2C9]
* {{UCSC gene info|CYP2C9}}

{{PDB Gallery|geneid=1559}}
{{Cytochrome P450}}
{{Enzymes}}
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{{Authority control}}

{{DEFAULTSORT:Cyp2c9}}
[[Category:Cytochrome P450|2]]