Alternative titles; symbols
HGNC Approved Gene Symbol: CYP2C19
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:94,762,681-94,855,547 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Clopidogrel, impaired responsiveness to | 609535 | Autosomal recessive | 3 |
| Mephenytoin poor metabolizer | 609535 | Autosomal recessive | 3 | |
| Omeprazole poor metabolizer | 609535 | Autosomal recessive | 3 | |
| Proguanil poor metabolizer | 609535 | Autosomal recessive | 3 |
CYP2C19 is a clinically important enzyme (EC 1.14.13.80) that metabolizes a wide variety of drugs, including the anticonvulsant mephenytoin, anti-ulcer drugs such as omeprazole, certain antidepressants, and the antimalarial drug proguanil. Mutation in the CYP2C19 gene causes poor metabolism of these drugs (see 609535) (Blaisdell et al., 2002).
Shephard et al. (1989) isolated a cDNA encoding CYP2C19, a novel member of the P450IIC subfamily in man. Northern blot hybridization of RNA isolated from human livers showed a 10-fold interindividual variation in the expression of the gene, suggesting that expression may be constitutive and not greatly influenced by environmental factors. The finding is in contrast to that with the CYP2A subfamily (see 122720), in which members exhibit a 1,000-fold interindividual variation in level of expression.
By the summer of 1986, according to Nebert et al. (1987), information in the form of full-length cDNA nucleotide sequence and/or amino acid sequence had been collected on 56 P450 gene products from 1 prokaryote and 8 eukaryotic species. Nebert et al. (1987) made recommendations on nomenclature. On the basis of amino acid similarities and differences, they recognized at least 8 mammalian P450 gene families, with at least 5 subfamilies in the P450II family and 2 subfamilies in the P450 XI family. The gene families, indicated by Nebert et al. (1987) with Roman numerals, are I, II, III, IV, XI, XVII, XIX and XXI. The choice of numbers for the last 4, which are involved in steroid metabolism, are derived from previous enzyme names: XIB is mitochondrial 11-beta-hydroxylase (610613); XIA is mitochondrial cholesterol side-chain cleavage enzyme (118485) coded by chromosome 15; XVII is steroid 17-alpha-hydroxylase (609300) coded by chromosome 10; XIX is aromatase (107910) coded by chromosome 15; and XXI is 21-hydroxylase (613815) coded by chromosome 6p. The IIC subfamily, which includes CYP2C19, is composed of a group of 'constitutively expressed' genes, some phenobarbital-induced genes, and several genes associated with sex-specific expression. This subfamily maps to chromosome 10q in man; the homologous loci are on mouse chromosome 19 (Nebert et al., 1987).
Studies of Wrighton et al. (1993) and of Goldstein et al. (1994) demonstrated a correlation between the levels of CYP2C19 protein and microsomal S-mephenytoin 4-prime-hydroxylase activity in human liver.
Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 2C19 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) concluded that their findings showed that expression of genes for cytochrome P450 monooxgenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs.
By somatic cell hybridization and in situ hybridization, Riddell et al. (1987) and Spurr et al. (1987) assigned a gene for the cytochrome P450 with mephenytoin 4-prime-hydroxylase activity (CYP2C) to chromosome 10q24.1-q24.3. Meehan et al. (1988) mapped the mouse cluster of genes to a region of chromosome 19 that appears to be homologous with the region of human chromosome 10 containing the CYP2C locus. Seven or 8 genes were clustered in a small area of 1 cM. Meehan et al. (1988) found that the CYP2C gene family in the mouse segregates to within 1-2 cM of a locus-controlling constitutive aryl hydrocarbon hydroxylase activity. Although apparent recombination might suggest that the control of AHH activity is mediated by a different but closely linked locus, Meehan et al. (1988) were of the opinion that AHH activity is encoded by the P450-2C genes. Man contains fewer genes in this cluster than do mice and rats. Sequence comparison suggests nonorthology of human cDNA clones to sequenced rat forms of the enzyme, raising an important question as to the appropriateness of the rodent model for human P450 function, in carcinogenesis, for example.
By analysis using Southern blot hybridization of DNA from a panel of 9 independent human-rodent somatic cell hybrids, Shephard et al. (1989) demonstrated that the CYP2C gene is located on human chromosome 10.
Using fluorescence in situ hybridization, Inoue et al. (1994) localized 3 genes of the CYP2C subfamily, CYP2C8 (601129), CYP2C9 (601130), and CYP2C10, to chromosome 10q24.1. Using a combination of STS and restriction mapping to characterize YAC clones, Gray et al. (1995) constructed a 2.4-Mb physical map that incorporated the CYP2C gene cluster. They found that the cluster spans approximately 500 kb on proximal 10q24 and comprises 4 genes arranged in the following order and orientation: Cen--RBP4 (180250)--CYP2C18 (601131)--CYP2C19--CYP2C9--CYP2C8--Tel. Primers specific for CYP2C10 gave no PCR product from either YACs or human genomic DNA, suggesting either PCR failure or that CYP2C10 is either frequently deleted or does not exist in the genome and is a cloning artifact. Subsequent Southern blot analysis implied the latter. Given that the CYP2C9 and CYP2C10 sequences show only 2 base differences in the coding region while showing marked difference in the 3-prime untranslated sequence, it seems likely that CYP2C10 is a cloning artifact derived from CYP2C9. Gray et al. (1995) concluded that there are no other CYP2C genes in the 10q24 cluster than the 4 mentioned. The close proximity of the serum retinol binding protein gene, RBP4, has its counterpart in the mouse where these genes are linked on chromosome 19.
Drug Metabolism
CYP2C19 is the cytochrome P450 enzyme that is the site of the defect in metabolism of mephenytoin and a number of other drugs. Studies of Wrighton et al. (1993) and of Goldstein et al. (1994) had demonstrated a correlation between the levels of CYP2C19 protein and microsomal S-mephenytoin 4-prime-hydroxylase activity in human liver. The molecular defect in CYP2C19 responsible for the poor metabolizer phenotype was identified by de Morais et al. (1994) and is referred to as the CYP2C19*2 allele (124020.0001).
De Morais et al. (1994) identified a novel mutation in the CYP2C19 gene, CYP2C19*3, which resulted in a premature termination codon (W212X; 124020.0003). Seven Japanese poor metabolizers who were not homozygous for CYP2C19*2 were either homozygous for CYP2C19*3 or heterozygous for the 2 defective alleles. CYP2C19*2 and CYP2C19*3 accounted for 100% of the available Japanese poor metabolizers (34 alleles), with CYP2C19*2 representing 25 alleles and CYP2C19*3 representing the remaining 9 alleles. The CYP2C19*3 allele was not detected in 9 Caucasian poor metabolizers.
Using direct sequencing and subcloning, Ohkubo et al. (2006) identified a novel mutation in the CYP2C19 gene, a 639C-G transversion which overlaps with the BamHI recognition site and thus was considered to be CYP2C19*3 by PCR-RFLP. Ohkubo et al. (2006) noted that many population studies use only PCR-RFLP, and suggested that alleles that have been identified as CYP2Y19*3 may include other mutations and should be confirmed by sequence analysis.
Proguanil, which is metabolized in the liver to its active form, cycloguanil, is recommended for malaria chemoprophylaxis in the face of chloroquine resistance in Plasmodium falciparum. Kaneko et al. (1997) noted that proguanil and mephenytoin metabolisms cosegregate, suggesting that poor mephenytoin metabolizers would also show poor therapeutic efficacy of proguanil. Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 and CYP2C19*3 mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C19*2 allele represented 698 of 986 alleles (70.6%), and the CYP2C19*3 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. By analyzing serum concentrations of proguanil and cycloguanil, Kaneko et al. (1997) found that the CYP2C19 genotype predicted the proguanil metabolism phenotype of all 20 patients examined. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population.
Genetic polymorphism in the metabolism of the anticonvulsant drug mephenytoin exhibits marked racial heterogeneity, with a poor metabolizer (PM) phenotype representing 13 to 23% of Asian populations, but only 2 to 5% of Caucasian populations. Two defective CYP2C19 alleles, CYP2C19*2 and CYP2C19*3, account for more than 99% of Asian PM alleles but only approximately 87% of Caucasian PM alleles. Ferguson et al. (1998) identified a defect in the initiation codon, CYP2C19*4 (124020.0004), accounting for an additional 3% of the defective alleles in Caucasians.
Ibeanu et al. (1998) reported the CYP2C19*5 allele, which is caused by an arg433-to-trp mutation (R433W; 124020.0002) in the heme-binding region. The frequency of the allele was estimated to be low in Chinese and Caucasians. The mutation abolished activity of recombinant enzyme toward S-phenytoin and tolbutamide. The nomenclature for the CYP2C19 alleles used by Ibeanu et al. (1998) was based on recommendations made by Daly et al. (1996). The wildtype allele reported by Romkes et al. (1991) was designated CYP2C19*1A. A second wildtype allele, described by Richardson et al. (1995), was designated CYP2C19*1B. Other alleles were designated CYP2C19*2, CYP2C19*3, and CYP2C19*4. Two variant CYP2CP19*5 alleles were termed 5A and 5B. The alleles numbered 2, 3, 4, 5A, and 5B yielded inactive enzymes.
Blaisdell et al. (2002) analyzed genomic DNA obtained from cell lines of 92 healthy individuals from 3 different racial groups of varied ethnic background, including Caucasians, Asians, and Africans, and identified 39 SNPs in the CYP2C19 gene. Expression of those SNPs producing coding changes in a bacterial expression system, followed by S-mephenytoin hydroxylation assays, revealed 3 potentially defective alleles present only in individuals of African descent.
Liou et al. (2006) investigated the frequencies of the poor and ultrarapid metabolizer-associated alleles of 5 cytochrome P450 genes in 180 Han Chinese volunteers in Taiwan and found that more than 50% of the CYP2C19 and CYP2D6 (124030) genotypes were associated with the intermediate metabolizer phenotype. Liou et al. (2006) suggested that this might explain why drug dosages used in clinical trials with east Asian participants are usually lower than those used in trials with western participants.
Clopidogrel, used to inhibit adenosine diphosphate-induced platelet aggregation, is a prodrug that must be metabolized in the liver by several CYP proteins to become active. Mega et al. (2009) tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. The authors then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1,477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38. Mega et al. (2009) found that in healthy subjects who were treated with clopidogrel, carriers of at least 1 CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P less than 0.001). Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval, 1.07 to 2.19; p = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs 0.8%; hazard ratio, 3.09; 95% confidence interval, 1.19 to 8.00; p = 0.02). Mega et al. (2009) concluded that among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Simon et al. (2009) studied 2,208 patients consecutively enrolled in a nationwide French registry who presented with an acute myocardial infarction and received clopidogrel therapy. They then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1; 171050), metabolic activation (CYP3A5, 605325, and CYP2C19), and biologic activity (P2RY12, 600515 and ITGB3, 173470) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected SNPs in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with 2 variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wildtype genotype (CC at nucleotide 3435) (15.5% vs 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval, 1.20 to 2.47). Patients carrying any 2 CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs 13.3%; adjusted hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.58). Among the 1,535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with 2 CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% confidence interval, 1.71 to 7.51). Simon et al. (2009) concluded that among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not.
Taubert et al. (2009) found that clopidogrel was not biotransformed into the active 2-oxo-clopidogrel when incubated with CYP2C19 in human microsomes. In contrast, omeprazole was transformed into its active form in the same system. Taubert et al. (2009) concluded that SNPs in the CYP2C19 gene may represent only tags for the true causal gene variant involved in clopidogrel activation.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the 3 combined genotypes, 1 for predicted CYP2C19 poor metabolizers (CYP2C19*2/CYP2C19*3) and 2 for predicted high levels of CYP2E1 (124040) (CYP2E1*5B and CYP2E1*6) transcription, were significantly lower in the Chinese Kazakh (7.5%, 19.6%, and 28.0%, respectively) and Uygur (8.1%, 22.8%, and 33.6%) populations compared to the Chinese Han population (16.5%, 35.9%, and 44.7%). The findings suggested that disease susceptibilities or drug responses associated with enzyme activities of CYP2C19 and CYP2E1 may differ between ethnic populations of mainland China.
This allelic variant is also known as CYP2C19*2 and CYP2C19m1.
The principal defect in CYP2C19 responsible for the S-mephenytoin poor metabolizer (PM) phenotype (609535) was found by de Morais et al. (1994) to be a G-to-A mutation at nucleotide 681 in exon 5 that created an aberrant splice site. The change altered the reading frame of the mRNA starting with amino acid 215 and produced a premature stop codon 20 amino acids downstream, resulting in a truncated, nonfunctional protein. De Morais et al. (1994) demonstrated that 7 of 10 Caucasian and 10 of 17 Japanese poor metabolizers were homozygous for this defect. The inheritance of the deficient allele was found to be concordant with that of the PM trait. To determine the nature of the defect, since the genomic sequence of CYP2C19 was not yet known, de Morais et al. (1994) developed primers for the intron 4/exon 5 junction empirically. This involved the use of multiple primers for intron 4 based on the sequence of this region in CYP2C9, a closely related gene that shows 95% similarity to CYP2C19 in the upstream region and several exons, and a specific reverse primer for exon 5 of CYP2C19. Because of the aberrant splice site, a 40-bp deletion occurred at the beginning of exon 5 (from bp 643 to bp 682), resulting in deletion of amino acids 215 to 227. The truncated protein had 234 amino acids and would be catalytically inactive because it lacked the heme-binding region. De Morais et al. (1994) developed a simple PCR-based test for the defective CYP2C19 allele.
Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 and CYP2C19*3 (124020.0003) mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C19*2 allele represented 698 of 986 alleles (70.6%), and the CYP2C19*3 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. Further studies showed that homozygosity or compound heterozygosity for the mutations were associated with poor metabolism of proguanil, which is recommended for malaria chemoprophylaxis. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population.
Among 1,419 patients with acute coronary syndrome on dual antiplatelet treatment, including clopidogrel and aspirin, Giusti et al. (2007) found an association between carriers of the CYP2C19*2 polymorphism and increased residual platelet reactivity, as evaluated by platelet aggregation studies. The active metabolite of clopidogrel arises from complex biochemical reactions involving several P450 isoforms, including CYP2C19.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequency of the CYP2C19*2 allele was significantly lower in the Kazakh and Uygur populations (15.4% and 16.1%, respectively) compared to the Han population (28.8%).
This allelic variant is also known as CYP2C19*5.
In a Chinese individual of the Bai ethnic group who exhibited the poor mephenytoin metabolizer phenotype (609535), Xiao et al. (1997) identified compound heterozygosity for the CYP2C19m1 allele (124020.0001) and a novel C-to-T mutation at nucleotide 1297 in exon 9 of the CYP2C19 gene, resulting in an arg433-to-trp (R433W) substitution in the heme-binding region.
Ibeanu et al. (1998) also reported the CYP2C19*5 variant and estimated that the frequency of the allele is low in Chinese and Caucasians. The mutation abolished activity of recombinant enzyme toward S-mephenytoin and tolbutamide.
This allelic variant is also known as CYP2C19*3 and CYP2C19m2.
De Morais et al. (1994) identified a G-to-A mutation at nucleotide 636 in exon 4 of the CYP2C19 gene in Japanese poor metabolizers (609535). The mutation resulted in a premature termination codon (trp212 to ter; W212X).
Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 (124020.0001) and CYP2C19*3 mutations in 493 individuals from 2 of the 80 islands of Vanuatu, where malaria is endemic. The CYP2C19*2 allele represented 698 of 986 alleles (70.6%), and the CYP2C19*3 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. Further studies showed that homozygosity or compound heterozygosity for the mutations were associated with poor metabolism of proguanil, which is recommended for malaria chemoprophylaxis. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the CYP2C19*3 allele were similar among the 3 groups (7.2%, 8.0%, and 9.4%, respectively) and higher than that reported in Caucasians (0%).
This allelic variant is also known as CYP2C19*4.
Ferguson et al. (1998) identified an A-to-G mutation in the initiation codon of CYP2C19, resulting in a met1-to-val substitution, in Caucasian poor metabolizers (609535). The frequency of the allele in Caucasians was 0.6%. Expression studies and in vitro transcription/translation assays confirmed that CYP2C19*4 represents a defective allele.
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