Biology:CYP2C9

From HandWiki
(Redirected from Biology:CYP2C9*3)
Short description: Enzyme protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2] The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.[3]

Function

CYP2C9 is a crucial cytochrome P450 enzyme, which plays a significant role in the metabolism, by oxidation, of both xenobiotic and endogenous compounds.[3] 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.[3] 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 drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids, converting these fatty acids to a wide range of biologically active products.[4][5]

In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide (EETs) stereoisomer sets: 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 metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers).[6] 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).[5]

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 acids 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.[7][8][9][10] 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 acids metabolites caused by dietary omega-3 fatty acids.[7][10][11]

CYP2C9 may also metabolize linoleic acid to the potentially very toxic products, vernolic acid (also termed leukotoxin) and coronaric 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.[5]

Pharmacogenomics

The CYP2C9 gene is highly polymorphic.[12] At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity.[12] 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.[13][14] Information about how human genetic variation of CYP2C9 affects response to medications can be found in databases such PharmGKB,[15] Clinical Pharmacogenetics Implementation Consortium (CPIC).[16]

The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant.[17] Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label.[18][19] 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),[20] causing reductions in enzyme activity of 30% and 80%, respectively.[12]

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.[21] 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).[22][23] 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.[24]

CYP2C9*3 reflects an Ile359-Leu (I359L) change in the amino acid sequence,[25] and also has reduced catalytic activity compared with the wild type (CYP2C9*1) for substrates other than warfarin.[26] 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

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.[12]

CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p. Leu90Pro, rs72558187).[12] CYP2C9*13 prevalence is approximately 1% in the Asian population,[27] but in Caucasians this variant prevalence is almost zero.[28] 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.[27] 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.[12] (As of 2020) the evidence level for CYP2C9*13 in the PharmVar database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive.[17]

Additional variants

Not all clinically significant genetic variant alleles have been registered by PharmVar. 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.[29] 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.[30] 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.[31] 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.[32] 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.[33][34]

Ligands

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,[35][36] phenethyl isothiocyanate,[37] medroxyprogesterone acetate[38] and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[39]

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.[40]
  • Moderate being one that causes at least a 2-fold increase in the plasma AUC values, or a 50–80% decrease in clearance.[40]
  • 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.[40][41]
Selected inducers, inhibitors and substrates of CYP2C9
Substrates Inhibitors Inducers

Strong

Moderate

Weak

Unspecified potency

Strong

Weak

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 acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[5] 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 pages).[5] 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 acids metabolites caused by dietary omega-3 fatty acids, eicosapentaenoic acids and EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[7][10][11]

See also

  • Cytochrome P450 oxidase

References

  1. ↑ "Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily". Biochemistry 30 (13): 3247–3255. April 1991. doi:10.1021/bi00227a012. PMID 2009263. 
  2. ↑ "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. September 1994. doi:10.1007/BF01874052. PMID 7841444. 
  3. ↑ 3.0 3.1 3.2 Template:NCBI RefSeq This article incorporates text from this source, which is in the public domain.
  4. ↑ "Clinical and toxicological relevance of CYP2C9: drug-drug interactions and pharmacogenetics". Annual Review of Pharmacology and Toxicology 45: 477–494. 2005. doi:10.1146/annurev.pharmtox.45.120403.095821. PMID 15822186. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 (4): 356–365. April 2015. doi:10.1016/j.bbalip.2014.07.020. PMID 25093613. 
  6. ↑ "CYP-eicosanoids – a new link between omega-3 fatty acids and cardiac disease?". Prostaglandins & Other Lipid Mediators 96 (1–4): 99–108. November 2011. doi:10.1016/j.prostaglandins.2011.09.001. PMID 21945326. 
  7. ↑ 7.0 7.1 7.2 "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews 66 (4): 1106–1140. October 2014. doi:10.1124/pr.113.007781. PMID 25244930. 
  8. ↑ "Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer". Progress in Lipid Research 53: 108–123. January 2014. doi:10.1016/j.plipres.2013.11.003. PMID 24345640. 
  9. ↑ "Soluble epoxide hydrolase: A potential target for metabolic diseases". Journal of Diabetes 8 (3): 305–313. May 2016. doi:10.1111/1753-0407.12358. PMID 26621325. 
  10. ↑ 10.0 10.1 10.2 "The role of long chain fatty acids and their epoxide metabolites in nociceptive signaling". Prostaglandins & Other Lipid Mediators 113–115: 2–12. October 2014. doi:10.1016/j.prostaglandins.2014.09.001. PMID 25240260. 
  11. ↑ 11.0 11.1 "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. June 2014. doi:10.1194/jlr.M047357. PMID 24634501. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 "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. September 2019. doi:10.1016/j.jmoldx.2019.04.003. PMID 31075510. 
  13. ↑ "Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals". Molecular Diagnosis & Therapy 10 (1): 29–40. 2006. doi:10.1007/BF03256440. PMID 16646575. 
  14. ↑ "The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance". Current Clinical Pharmacology 2 (1): 93–109. Jan 2007. doi:10.2174/157488407779422302. PMID 18690857. 
  15. ↑ "PharmGKB" (in en). https://www.pharmgkb.org/gene/PA126/prescribingInfo. 
  16. ↑ "CYP2C9 CPIC guidelines" (in en-US). https://cpicpgx.org/gene/cyp2c9/. 
  17. ↑ 17.0 17.1 "PharmVar". https://www.pharmvar.org/gene/CYP2C9. 
  18. ↑ "Structural variation at the CYP2C locus: Characterization of deletion and duplication alleles". Human Mutation 40 (11): e37–e51. November 2019. doi:10.1002/humu.23855. PMID 31260137. 
  19. ↑ "PharmVar GeneFocus: CYP2C19". Clinical Pharmacology and Therapeutics 109 (2): 352–366. June 2020. doi:10.1002/cpt.1973. PMID 32602114. 
  20. ↑ "The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism". Pharmacogenetics 6 (4): 341–349. August 1996. doi:10.1097/00008571-199608000-00007. PMID 8873220. 
  21. ↑ "Cytochrome P450 in Pharmacogenetics: An Update". Pharmacogenetics. Advances in Pharmacology (San Diego, Calif.). 83. Academic Press. 2018. pp. 3–32. doi:10.1016/bs.apha.2018.04.007. ISBN 9780128133811. 
  22. ↑ "Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing". Clinical Pharmacology and Therapeutics 96 (5): 542–548. November 2014. doi:10.1038/clpt.2014.159. PMID 25099164. 
  23. ↑ "SLCO1B1 gene-polymorphism frequency in Russian and Nanai populations". Pharmacogenomics and Personalized Medicine 10: 93–99. 2017. doi:10.2147/PGPM.S129665. PMID 28435307. 
  24. ↑ "Association between the CYP2C9 polymorphism and the drug metabolism phenotype". Clinical Chemistry and Laboratory Medicine 42 (1): 72–78. January 2004. doi:10.1515/CCLM.2004.014. PMID 15061384. 
  25. ↑ CYP2C9 allele nomenclature
  26. ↑ 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
  27. ↑ 27.0 27.1 "Study of the Structural Pathology Caused by CYP2C9 Polymorphisms towards Flurbiprofen Metabolism Using Molecular Dynamics Simulation.". International Conference on Computational Systems – Biology and Bioinformatics. Communications in Computer and Information Science. 115. Berlin, Heidelberg: Springer. November 2010. pp. 26–35. doi:10.1007/978-3-642-16750-8_3. ISBN 978-3-642-16749-2. https://books.google.com/books?id=oHmqCAAAQBAJ&pg=PA27. 
  28. ↑ "rs72558187 allele frequency". National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/snp/rs72558187#frequency_tab.  This article incorporates text from this source, which is in the public domain.
  29. ↑ "Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study". Frontiers in Pharmacology 8: 347. 2017. doi:10.3389/fphar.2017.00347. PMID 28638342. 
  30. ↑ "A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose". PLOS Genetics 5 (3): e1000433. March 2009. doi:10.1371/journal.pgen.1000433. PMID 19300499. 
  31. ↑ "PharmGKB". https://www.pharmgkb.org/clinicalAnnotation/1043880397. 
  32. ↑ "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. June 2015. doi:10.1016/j.trsl.2014.11.006. PMID 25499099. 
  33. ↑ "Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers". Pharmacogenomics 15 (11): 1417–1421. August 2014. doi:10.2217/pgs.14.85. PMID 25303293. 
  34. ↑ "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. July 2012. doi:10.1007/s00228-012-1210-0. PMID 22294058. 
  35. ↑ "Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes". Drug Metabolism and Disposition 27 (2): 288–296. February 1999. PMID 9929518. 
  36. ↑ "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. February 2004. doi:10.1023/B:CEMN.0000012725.31108.4a. PMID 15049511. 
  37. ↑ "Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate". Drug Metabolism and Disposition 29 (8): 1110–1113. August 2001. PMID 11454729. 
  38. ↑ "Inhibitory effect of medroxyprogesterone acetate on human liver cytochrome P450 enzymes". European Journal of Clinical Pharmacology 62 (7): 497–502. July 2006. doi:10.1007/s00228-006-0128-9. PMID 16645869. 
  39. ↑ 39.0 39.1 39.2 39.3 39.4 "Mechanism of CYP2C9 inhibition by flavones and flavonols". Drug Metabolism and Disposition 37 (3): 629–634. March 2009. doi:10.1124/dmd.108.023416. PMID 19074529. 
  40. ↑ 40.00 40.01 40.02 40.03 40.04 40.05 40.06 40.07 40.08 40.09 40.10 40.11 40.12 40.13 40.14 40.15 40.16 40.17 40.18 40.19 40.20 40.21 40.22 40.23 40.24 40.25 40.26 40.27 40.28 40.29 40.30 40.31 40.32 40.33 40.34 40.35 40.36 40.37 40.38 40.39 40.40 40.41 40.42 40.43 40.44 40.45 40.46 40.47 "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. 2007. http://medicine.iupui.edu/flockhart/table.htm. 
  41. ↑ 41.0 41.1 41.2 41.3 41.4 "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm. 
  42. ↑ 42.0 42.1 42.2 42.3 "In silico metabolism studies of dietary flavonoids by CYP1A2 and CYP2C9". Food Research International 50: 102–110. 2013. doi:10.1016/j.foodres.2012.09.027. 
  43. ↑ 43.00 43.01 43.02 43.03 43.04 43.05 43.06 43.07 43.08 43.09 43.10 43.11 43.12 43.13 43.14 43.15 43.16 43.17 43.18 43.19 FASS (drug formulary): "Facts for prescribers (Fakta för förskrivare)" (in sv). Swedish environmental classification of pharmaceuticals. http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352. 
  44. ↑ "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. June 2005. doi:10.1124/dmd.105.003616. PMID 15764711. 
  45. ↑ "ketoprofen | C16H14O3". PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/3825#x301. 
  46. ↑ 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
  47. ↑ "CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin". Biochemical Pharmacology 70 (7): 1096–1103. October 2005. doi:10.1016/j.bcp.2005.07.007. PMID 16112652. 
  48. ↑ "Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants". Biochemical and Biophysical Research Communications 498 (3): 597–602. April 2018. doi:10.1016/j.bbrc.2018.03.028. PMID 29522717. 
  49. ↑ "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review". Drug Metabolism Reviews 46 (1): 86–95. February 2014. doi:10.3109/03602532.2013.849268. PMID 24160757. https://zenodo.org/record/1093138. 
  50. ↑ "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. May 2002. doi:10.1124/dmd.30.5.602. PMID 11950794. 
  51. ↑ "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. October 2001. PMID 11560871. 
  52. ↑ "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 (American Society for Pharmacology & Experimental Therapeutics (ASPET)) 41 (12): 2056–2065. December 2013. doi:10.1124/dmd.113.052639. PMID 23785064. 
  53. ↑ "Verapamil: Drug information. Lexicomp". https://www.uptodate.com/contents/verapamil-drug-information. 
  54. ↑ "Candesartan Tablet". 27 June 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8ceb5658-b03c-475d-9ef0-2cd0645191d3. 
  55. ↑ "Irbesartan Tablet". 4 September 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e8635a1c-ae06-4e23-99f7-e704f91d6f43. 
  56. ↑ "Edarbi – azilsartan kamedoxomil tablet". 25 January 2018. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52b27c75-9f5a-4816-bafd-dace9d7d2063. 
  57. ↑ "Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity". Food and Chemical Toxicology 48 (1): 429–435. Jan 2010. doi:10.1016/j.fct.2009.10.041. PMID 19883715. 
  58. ↑ "Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B". Bioorganic & Medicinal Chemistry 13 (20): 5819–5825. October 2005. doi:10.1016/j.bmc.2005.05.071. PMID 16084098. 
  59. ↑ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. 26 May 2021. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
  60. ↑ "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. May 2015. doi:10.3109/00498254.2014.990948. PMID 25470432. 
  61. ↑ "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. October 2010. doi:10.1111/j.1365-2796.2010.02257.x. PMID 20698928. 
  62. ↑ 62.0 62.1 "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. February 2002. doi:10.1007/s00228-001-0399-0. PMID 11936702. 
  63. ↑ "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrobial Agents and Chemotherapy 47 (11): 3464–3469. November 2003. doi:10.1128/AAC.47.11.3464-3469.2003. PMID 14576103. 
  64. ↑ "In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil". Drug Metabolism and Disposition 28 (6): 664–671. June 2000. PMID 10820139. 
  65. ↑ "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. 1 January 2012. doi:10.2133/dmpk.DMPK-11-RG-107. PMID 22166891. 
  66. ↑ "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics 10 (4): 277. December 2018. doi:10.3390/pharmaceutics10040277. PMID 30558213. 
  67. ↑ "Resveratrol stereoselectively affected (±)warfarin pharmacokinetics and enhanced the anticoagulation effect". Scientific Reports 10 (1): 15910. September 2020. doi:10.1038/s41598-020-72694-0. PMID 32985569. Bibcode: 2020NatSR..1015910H. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:CYP2C9&oldid=3582470#Metabolizer_phenotypes"