Molecule Information

General Information of the Molecule (ID: Mol01860)

• Name: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) ,Homo sapiens
• Synonyms: CYP2C19
• Molecule Type: Protein
• Gene Name: CYP2C19
• Gene ID: 1557
• Location: chr10:94,762,681-94,855,547[+]
• Sequence:
  MDPFVVLVLCLSCLLLLSIWRQSSGRGKLPPGPTPLPVIGNILQIDIKDVSKSLTNLSKI
  YGPVFTLYFGLERMVVLHGYEVVKEALIDLGEEFSGRGHFPLAERANRGFGIVFSNGKRW
  KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS
  IIFQKRFDYKDQQFLNLMEKLNENIRIVSTPWIQICNNFPTIIDYFPGTHNKLLKNLAFM
  ESDILEKVKEHQESMDINNPRDFIDCFLIKMEKEKQNQQSEFTIENLVITAADLLGAGTE
  TTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRGHMPYTDAVVHEVQRYID
  LIPTSLPHAVTCDVKFRNYLIPKGTTILTSLTSVLHDNKEFPNPEMFDPRHFLDEGGNFK
  KSNYFMPFSAGKRICVGEGLARMELFLFLTFILQNFNLKSLIDPKDLDTTPVVNGFASVP
  PFYQLCFIPV
• Function: A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position. Catalyzes the epoxidation of double bonds of PUFA. Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol. Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position.
• Uniprot ID: CP2CJ_HUMAN
• Ensembl ID: ENSG00000165841
• HGNC ID: HGNC:2621

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Clopidogrel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Coronary artery disease [1]

• Resistant Disease: Coronary artery disease [ICD-11: BA8Z.0]
• Resistant Drug: Clopidogrel
• Molecule Alteration: SNP; CYP2C19*2
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood sample; .
• Experiment for Molecule Alteration: Genetic analysis assay
• Experiment for Drug Resistance: Platelet aggregation test assay
• Mechanism Description: Among the 72 patients studied, 32.6% were carriers of CYP2C19*2 loss-of-function allele. This allele was found to be more common but not significantly so from the controls (27.7%). The loss-of-function genotypes (*2/*2 or *2/*1) of CYP2C19 were seen to be significantly higher in clopidogrel semi-responders compared to responders (72.9% vs 34.3%, P = 0.0023, respectively). Similarly, significantly higher frequency of the mutant *2 allele of CYP2C19 was observed in clopidogrel semi-responders than in responders (43.2% vs 21.4%, P = 0.007).

Disease Class: Acute myocardial infarction [2]

• Resistant Disease: Acute myocardial infarction [ICD-11: BA41.1]
• Resistant Drug: Clopidogrel
• Molecule Alteration: SNP; CYP2C19*2+CYP2C19*3
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We defined CYP2C19*2 and CYP2C19*3 as CYP2C19 loss-of-function alleles (LoFA), indicating possible clopidogrel resistance.

Disease Class: Peripheral arterial disease [3]

• Resistant Disease: Peripheral arterial disease [ICD-11: BD4Z.0]
• Resistant Drug: Clopidogrel
• Molecule Alteration: SNP; .
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Whole blood; .
• Experiment for Drug Resistance: VerifyNow P2Y12 assay
• Mechanism Description: Clopidogrel is a pro-drug requiring cytochrome P450 (CYP) 2C19 enzyme to be oxidised to its active form.CYP 2C19 genetic polymorphism may result clopidogrel resistance.

Disease Class: Hypo-attenuated leaflet thickening [4]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Resistant Drug: Clopidogrel
• Molecule Alteration: SNP; rs4244285+rs4986893+rs28399504+rs56337013+rs72552267+rs72558186+rs12248560
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 11

Myocardial infarction [ICD-11: BA41]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Peripheral blood
• The Specified Disease: Myocardial infarction
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.35E-02; Fold-change: 1.96E-01; Z-score: 4.18E-01

Coronary artery disease [ICD-11: BA8Z]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Peripheral blood
• The Specified Disease: Coronary artery disease
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.83E-01; Fold-change: -8.91E-02; Z-score: -4.03E-01

References

• Ref 1: Association of CYP2C19, CYP3A5 and GPIIb/IIIa gene polymorphisms with Aspirin and Clopidogrel Resistance in a cohort of Indian patients with Coronary Artery Disease .Int J Lab Hematol. 2015 Dec;37(6):809-18. doi: 10.1111/ijlh.12416. Epub 2015 Aug 12. 10.1111/ijlh.12416
• Ref 2: Assessment of Risk Factors for Drug Resistance of Dual Anti Platelet Therapy After PCI .Clin Appl Thromb Hemost. 2022 Jan-Dec;28:10760296221083674. doi: 10.1177/10760296221083674. 10.1177/10760296221083674
• Ref 3: CYP2C19 Polymorphism is Associated With Amputation Rates in Patients Taking Clopidogrel After Endovascular Intervention for Critical Limb Ischaemia .Eur J Vasc Endovasc Surg. 2019 Sep;58(3):373-382. doi: 10.1016/j.ejvs.2019.02.011. Epub 2019 Aug 5. 10.1016/j.ejvs.2019.02.011
• Ref 4: Gene polymorphisms in dual antiplatelet therapy and the presence of hypo-attenuated leaflet thickening after transcatheter aortic valve replacement .J Thromb Thrombolysis. 2018 Apr;45(3):463-465. doi: 10.1007/s11239-018-1636-z. 10.1007/s11239-018-1636-z