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Overview
| Alternate Names: | OTTHUMP00000020132; OTTHUMP00000059588; S-mephenytoin 4-hydroxylase; cytochrome P-450 II C; cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 19; cytochrome p450; flavoprotein-linked monooxygenase; mephenytoin 4'-hydroxylase; microsomal monooxygenase; xenobiotic monooxygenase |
|---|---|
| Alternate Symbols: | CPCJ; CYP 2C; CYP2C; P450C2C; P450IIC19 |
| PharmGKB Accession Id: | PA124 |
Details
| Cytogenetic Location: | chr10 : q23.33 |
|---|---|
| GP mRNA Boundary†: | chr10 : 96512453 - 96602661 |
| GP Gene Boundary†: | chr10 : 96502453 - 96605661 |
| Strand: | plus |
| Product Name: | OTTHUMP00000059588, S-mephenytoin 4-hydroxylase, cytochrome P-450 II C, cytochrome P450, family 2, subfamily C, polypeptide 19, cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 19, flavoprotein-linked monooxygenase, mephenytoin 4'-hydroxylase, microsomal monooxygenase, xenobiotic monooxygenase |
†
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped
onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries
by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for
potential regulatory regions.
Introduction
Cytochrome P450 2C19, CYP2C19, is responsible for the metabolism of a large number of clinically relevant drugs, including the anticonvulsant mephenytoin, anti-ulcer drugs such as omeprazole, certain antidepressants, and the antimalarial drug proguanil [reviewed by Desta et al, PMID: 12222994]. The drug-interaction table maintained by the COBRA group has a regularly updated list of drugs that interact with CYP2C19 categorized into substrates, inhibitors and inducers, and links to the supporting literature. CYP2C19 protein is mainly present in the liver although activity has been observed in intestine [PMID: 11181505].
A variant response to mephenytoin 4-hydroxylation lead to the phenotypic classification of individuals into poor metabolizers (PM) and extensive metabolizers (EM). It was observed that the PM phenotype was more common in Asians than Whites [PMID: 4042523]. Genetic variation in CYP2C19 was shown to be responsible for the PM phenotype [PMID: 8195181]. The two main haplotypes, CYP2C19*2 and CYP2C19*3, account for 99% of PM in Asians and approximately 87% of White PMs [PMID: 9435198]. Over 20 other variants and haplotypes have been reported. The Human Cytochrome P450 Allele Nomenclature Committee website lists all of the reported genetic variants and their approved haplotype names. The AmpliChip CYP450 Test (Roche Diagnostics) is an FDA approved diagnostic test that detects variation in CYP2C19 and CYP2D6.
In-Depth Annotations (
)
-
rs4986893
at chr10:96530400
in
CYP2C19
This variant results in a premature termination codon in cDNA; defining variant for CYP2C19*3. -
rs4244285
at chr10:96531606
in
CYP2C19
Introduces a splicing defect resulting in a truncated, non-functional protein responsible for the poor metabolizer phenotype; defining variant for CYP2C19*2. -
rs4244285
at chr10:96531606
in
CYP2C19
This loss-of-function variant CYP2C19*2 was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.- Variant Name:
- CYP2C19*2; CYP2C19:681G>A
- Related Drugs:
- clopidogrel
- Related Diseases:
- Cardiovascular Diseases
- Evidence:
-
PMID:19706858
Curated Annotations (
)
-
rs11188072
at chr10:96509051
in
CYP2C19
This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.- Variant Name:
- CYP2C19: -3402C>T
- Related Drugs:
- amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
- Evidence:
-
PMID:16413245
PMID:17625515
PMID:18294333
-
rs11188072
at chr10:96509051
in
CYP2C19
Risk or phenotype-associated allele: T Phenotype: The CYP2C19*17 allele was associated with significantly increased metabolism of imipramine. Study size: 178 Study population/ethnicity: Psychiatric patients aged 18-65 with a score of greater than or equal to 17 on the Hamilton Rating Scale for Depression. Significance metric(s): p = 0.035 Type of association: PK- Variant Name:
- part of CYP2C19*17; CYP2C19:(-3402)C>T; CYP2C19: -3402C>T
- Related Drugs:
- imipramine
- Evidence:
-
PMID:19884907
-
rs12248560
at chr10:96511647
in
CYP2C19
This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.- Variant Name:
- CYP2C19: -806C>T
- Related Drugs:
- amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
- Evidence:
-
PMID:16413245
PMID:18024866
-
rs12248560
at chr10:96511647
in
CYP2C19
Risk or phenotype-associated allele: T Phenotype: The CYP2C19*17 allele was associated with significantly increased metabolism of imipramine. Study size: 178 Study population/ethnicity: Psychiatric patients aged 18-65 with a score of greater than or equal to 17 on the Hamilton Rating Scale for Depression. Significance metric(s): p = 0.035 Type of association: PK- Variant Name:
- part of CYP2C19*17; CYP2C19:(-806)C>T; CYP2C19: -806C>T
- Related Drugs:
- imipramine
- Evidence:
-
PMID:19884907
-
rs28399504
at chr10:96512453
in
CYP2C19
This allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. Based on the genotyping results the authors conclude that the defective nature of the CYP2C19*4 allele is shown by the fact that two Caucasian poor metabolizers were heterozygous for CYP2C19*2/CYP2C19*4. In vitro experiments showed no expression of CYP2C19*4 cDNA. The study calculated that the frequency of the CYP2C19*4 allele in Caucasians was 0.6%.- Variant Name:
- CYP2C19*4; 1A>G; 99C>T; 80161A>G
- Related Drugs:
- mephenytoin
- Evidence:
-
PMID:9435198
-
rs28399504
at chr10:96512453
in
CYP2C19
Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.- Variant Name:
- CYP2C19*4, CYP2C19:A1G
- Related Drugs:
- clopidogrel
- Related Diseases:
- Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
- Evidence:
-
PMID:19106083
-
rs41291556
at chr10:96525163
in
CYP2C19
This variant is the defining SNP for CYP2C19*8 and leads to decreased activity and poor metabolizer (PM) phenotype.This variant is associated with a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide in vitro.- Variant Name:
- CYP2C19:358T>C; 12711T>C; W120R; T358C
- Related Drugs:
- mephenytoin, tolbutamide
- Evidence:
-
PMID:10411572
-
rs17884712
at chr10:96525236
in
CYP2C19
This variant is the defining SNP for CYP2C19*9 and associated with a modest decrease in the V(max) for 4'-hydroxylation of S-mephenytoin in vitro.- Variant Name:
- CYP2C19:431G>A; R144H
- Related Drugs:
- mephenytoin
- Evidence:
-
PMID:12464799
-
rs4986893
at chr10:96530400
in
CYP2C19
Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.- Variant Name:
- CYP2C19*3, CYP2C19:G636A
- Related Drugs:
- clopidogrel
- Related Diseases:
- Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
- Evidence:
-
PMID:19106083
-
rs4986893
at chr10:96530400
in
CYP2C19
In contrast to other PPIs, esomeprazole-induced healing of GERD appears to be unrelated to the CYP2C19*3 variant.- Variant Name:
- CYP2C19*3
- Related Drugs:
- esomeprazole
- Related Diseases:
- Gastroesophageal Reflux
- Evidence:
-
PMID:16338278
-
rs6413438
at chr10:96531605
in
CYP2C19
This variant is the defining SNP for CYP2C19*10. This variant is associated with reduction in the metabolism of S-mephenytoin in vitro.- Variant Name:
- CYP2C19:680C>T; 19153C>T; P227L
- Related Drugs:
- mephenytoin
- Evidence:
-
PMID:12464799
-
rs4244285
at chr10:96531606
in
CYP2C19
Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.- Variant Name:
- CYP2C19*2, CYP2C19:G681A
- Related Drugs:
- clopidogrel
- Related Diseases:
- Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
- Evidence:
-
PMID:19106083
-
rs4244285
at chr10:96531606
in
CYP2C19
Subjects with acute coronary syndromes receiving treatment with clopidogrel and who carried two copies of CYP2C19 loss-of-function/reduced function alleles (two copies of CYP2C19*2; or one copy of CYP2C19*2 and one copy of CYP2C19*3, CYP2C19*4 or CYP2C19*8) had a relative increase of 53% in risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers. Subjects were participants in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMTI) 38. 97.6% of the study participants were Caucasian. In a separate cohort of healthy subjects treated with clopidogrel, carriers of at least one reduced-function CYP2C19 allele had significantly lower levels of clopidogrel's active metabolite and diminished platelet inhibition.- Variant Name:
- CYP2C19*2, CYP2C19:G681A
- Related Drugs:
- clopidogrel
- Related Diseases:
- Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
- Evidence:
-
PMID:19106084
-
rs4244285
at chr10:96531606
in
CYP2C19
In contrast to other PPIs, esomeprazole-induced healing of GERD appears to be unrelated to the CYP2C19*2 variant.- Variant Name:
- CYP2C19*2
- Related Drugs:
- esomeprazole
- Related Diseases:
- Gastroesophageal Reflux
- Evidence:
-
PMID:16338278
-
rs56337013
at chr10:96602485
in
CYP2C19
This variant is the defining SNP for CYP2C19*5 and contributes to the S-mephenytoin poor metabolizer phenotype in caucasians and chinese. The Arg433 to Trp mutation in the heme-binding region essentially abolishes CYP2C19 activity toward S-mephenytoin and tolbutamide.- Variant Name:
- CYP2C19:1297C>T; R433W
- Related Drugs:
- mephenytoin, tolbutamide
- Evidence:
-
PMID:10022751
Variant names are different names that have been used in the literature and other resources to
refer to the same variant.
Curated Information
The following genes are in curated knowledge about this gene.
| Gene | Relationship | Evidence | |
|---|---|---|---|
|
CYP3A5 |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other genes is available.
PharmGKB Curated Pathways
- Anti-estrogen Pathway (Tamoxifen PK)
- Antiplatelet Drug Clopidogrel Pathway (PK)
- Citalopram (PK)
- Cyclophosphamide Pathway (PK)
- Gefitinib Pathway (PK)
- Imatinib
- Imipramine/Desipramine Pathway (PK)
- Phenytoin PK Pathway
- Platelet Aggregation Pathway (PD)
- Proton Pump Inhibitor (PK)
- SSRI Fluoxetine Pathway (PK)
- Statin Pathway (Fluvastatin PK)
- Statin Pathway (PK)
- Warfarin Pathway (PK)
Reactome Pathways†
†
External pathways not curated by PharmGKB.
Curated Information
The following drugs are in curated knowledge about this gene.
| Drug Class | Relationship | Evidence | |
|---|---|---|---|
|
antidepressants |
|
Publications |
|
|
antipsychotics |
|
Publications |
|
|
antithrombotic agents |
|
Pathways |
|
|
Anxiolytics |
|
Publications |
|
|
glucocorticoids |
|
Publications |
|
|
hmg coa reductase inhibitors |
|
Pathways |
|
|
Proton pump inhibitors |
|
Publications |
|
|
xenobiotics |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other drugs is available.
Curated Information
The following diseases are in curated knowledge about this gene.
Non-Curated Information
A list of non-curated publications that mention this gene along with other diseases is available.
Curated Phenotype Datasets
These datasets are sorted alphabetically by title.
- Meperidine N-demethylation by endogenous CYP450 enzymes in human liver microsomes
- FA
Submitted by Mark J. Ratain, MD involving CYP2B6, CYP2C19, CYP3A4, , meperidine, mephenytoin and midazolam - Meperidine N-demethylation by human CYP450 isoforms
- FA
Submitted by Mark J. Ratain, MD involving CYP2B6, CYP2C18, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and meperidine
Additional Datasets
These datasets are minimally curated and are sorted alphabetically by title.
Downloads
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LinkOuts
- Entrez Gene ID:
- 1557
- OMIM Accession:
- 124020
- 609535
- UCSC Genome Browser ID:
- NM_000769
- Ref Seq NM Accession:
- NM_000769
- Ref Seq NP Accession:
- AAB59426
- AAI11847
- AAL31347
- AAL31348
- AAV41877
- BAD02827
- CAA46778
- CAH73444
- CAH74068
- NP_000760
- P33261
- Q16743
- Q767A3
- Ref Seq NT Accession:
- AC_000053
- AC_000142
- NC_000010
- NG_008384
- NT_030059
- NW_001838005
- NW_924884
- Web Resource:
- http://www.imm.ki.se/CYPalleles/cyp2c19.htm
- UniProtKB Accesssion:
- CP2CJ_HUMAN (P33261)
- Ensembl ID:
- ENSG00000165841
- GenAtlas ID:
- CYP2C19
- GeneCard ID:
- CYP2C19
- SOURCE ID:
- CYP2C19
Common Searches
Non-Curated Publications
A list of non-curated publications that mention this gene is available.