Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI) (original) (raw)
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Prevalence of CYP2C19 Genetic Polymorphism among Normal People and Patients with Hepatic Diseases
International Journal of Organ Transplantation Medicine, 2018
Background: Patients with hepatic diseases are treated with numerous drugs metabolized by cytochrome P450. Objective: To evaluate the frequencies of CYP2C19 variant alleles (*2, *3, and *17), genotypes, and phenotypes, and the relationship between the frequency of these alleles and the underlying hepatic diseases among patients with advanced liver diseases who were candidates for liver transplantation. Methods: The Study was conducted on 120 patients suffering from various hepatic disorders, candidates for liver transplantation, and 52 healthy volunteers. DNA was extracted from blood samples and analyzed by TaqMan SNP genotyping assay. The CYP2C19 genotypes were classified into poor, extensive, intermediate, and ultra-rapid metabolizer phenotypes. Results: Viral hepatitis was the most common cause of liver disease among studied patients. The frequencies of CYP2C19 alleles *1, *17, and *2 were 66.7% (160/240), 20.8% (50/240) and 12.5% (30/240), respectively. Allele CYP2C19*3 was not ...
Journal of Clinical Pharmacy and Therapeutics, 2019
What is known and objective: Genetic polymorphism is one of the most important factors responsible for interindividual and interethnic variability in drug response. Studies in major populations, ie, Caucasians, Asians, and Africans, have provided evidence of differences in the genotype frequencies of major drug-metabolizing enzyme cytochrome P450 (CYP). This study aimed to review systematically, all relevant articles related to the genetic polymorphisms in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in SouthEast and East Asian (SEEA) populations. Methods: Articles that report genetic polymorphisms, genotype frequencies and allele frequencies in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 were retrieved from the PubMed database. Results and discussions: A total of 86 studies that fulfilled the eligibility criteria representing different ethnic populations of SEEA, ie, Burmese, Chinese, Japanese, Karen ethnic minority, Korean, Malaysian, Philippino, Singaporean, Taiwanese, Thai, Indonesian, and Vietnamese, were included in the analysis. In general, the genotype frequencies across SEEA populations are comparable. The CYP2C9*1/*1 (69.3%-99.1%), *1/*3 (2.3%-20.1%) and *3/*3 (0%-2.2%) genotypes are reported in most SEEA populations. Six major CYP2C19 genotypes, ie, *1/*1 (6.25%-88.07%), *1/*2 (21.5%-86.46%), *1/*3 (0.8%-15.8%), *2/*2 (3.4%-14.5%), *2/*3 (0%-7.3%) and *3/*3 (0%-10.2%), are reported in most SEEA populations. Major CYP2D6 genotypes include *10/*10 (0%-69.6%), *1/*1 (0%-61.21%) and *1/*10 (0%-62.0%). Major CYP3A5 genotypes are *3/*3 (2.0%-71.4%), *1/*3 (16.0%-57.1%) and *1/*1 (0%-82.0%). Genotyping of abnormal genotypes of CYP2C9 (*1/*3), CYP2C19 (*1/*2, *1/*3), CYP3A5 (*1/*3) and CYP2D6 (*5/*10) associated with IM (Intermediate metabolizer) status, may be clinically beneficial in SEEA populations. Similarly, with CYP2C19 (*2/*2, *2/*3), CYP2D6 (*5/*5) linked to PM (Poor metabolizer), CYP2D6 (*10/*10, *1/*5 and to lesser extent *1/*4, *2/*5, *10/*41, *10/*49, *10/*14) and CYP3A5 (*1/*1) associated with EM (extensive metabolizer). What is new and conclusion: Sufficient number of studies has provided comparable results in general. This review suggests that comparable genotype frequencies of CYP2C9, CYP2C19, CYP2D6 and CYP3A5 exist among the SEEA populations. It is noted that more research data are reported from East Asians compared with SouthEast Asians. Concerned efforts are required to establish partnerships among SEEA countries that will ensure sufficient data from SouthEast Asian countries which will assist in establishing the databases for SEEA populations. Populations CYP2C9 genotypes, N, n (%) References
Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms
Biochemical and Biophysical Research Communications, 2002
Cytochrome P450 (CYP) 2C8 and 2C9 are polymorphic enzymes. The CYP2C8*3 and CYP2C9*2 are the major variant alleles in Caucasian populations. The enzymes encoded by these variant alleles have impaired function for the metabolism of several drug substrates. In the present study 1468 subjects that were used as population-based controls in the Stockholm Heart Epidemiology Program (SHEEP) were genotyped by allelic discrimination using a 5Õ-nuclease assay for CYP2C8*1, 2C8*3, 2C9*1, 2C9*2, and 2C9*3 variant alleles in which the frequencies appeared to be 0.91, 0.095, 0.83, 0.11, and 0.066, respectively. Approximately, 96% of the subjects with CYP2C8*3 allele also carried a CYP2C9*2 and 85% of the subjects that had CYP2C9*2 variant also carried a CYP2C8*3. The number of subjects carrying both of the CYP2C8*1*3 and CYP2C9*1*2 was 4.5-fold higher than expected. This strong association may be of importance especially for the metabolism of common substrates of CYP2C8 and CYP2C9 like arachidonic acid that produces physiologically active metabolites.
Allele frequency of CYP2C19 gene polymorphisms in a healthy Iranian population
Iranian Journal of …, 2005
Cytochrome P450 2C19 (CYP2C19) plays an important role in the metabolism and elimination of a wide range of medications. The polymorphisms of this enzyme give rise to substantial inter-individual and interethnic variability in drug excretion rates and final serum concentrations. For this reason, therapeutic responses and adverse drug reactions may vary from one person to another. In this study we determined genotypes of CYP2C19 in Iranian population to compare allele frequencies with previous findings in other ethnic groups. CYP2C19 (*1/*2/*3) allelic variants were determined in 200 unrelated healthy Iranian volunteers by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Six subjects (3%) were homozygous for CYP2C19*2, while 44 individuals (22%) were heterozygous. In the remainder (75%) no CYP2C19*2 was found. In addition, no CYP2C19*3 was detected in the population studied. Based on our data, there was no difference between frequency of CYP2C19 allelic variants in our study and other evaluated Caucasians (p > 0.05).
Scientific Reports, 2021
CYP2C9, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of 15–20% of clinically important drugs (warfarin, sulfonylureas, phenytoin, non-steroid anti-inflammatory drugs). To avoid adverse events and/or impaired drug-response, CYP2C9 pharmacogenetic testing is recommended. The impact of CYP2C9 polymorphic alleles (CYP2C9*2, CYP2C9*3) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C9*3 allele was associated with CYP2C9 functional impairment, and CYP2C9*2 influenced tolbutamide 4′-hydroxylase activity only in subjects with two polymorphic alleles, whereas the contribution of CYP2C8*3 was not confirmed. In addition to CYP2C9 genetic polymorphisms, non-genetic factors (co-medication with CYP2C9-specific inhibitors/inducers and non-specific factors including amoxicillin + clavulanic acid therapy or chronic alcohol consumption) contributed ...
Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes
The Pharmacogenomics Journal, 2013
To determine CYP2C19 and CYP2C8 allele frequencies, 28 coding and/or functional variants were genotyped in 1250 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish (AJ) individuals. The combined CYP2C19 variant allele frequencies ranged from B0.30 to 0.41; however, the CYP2C8 frequencies were much lower (B0.04 --0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies 40.5%. Notably, the 2C19*17-2C9*1-2C8*2 haplotype was identified among African-Americans (8%) and Hispanics (2%), indicating that CYP2C19*17 does not always tag a CYP2C haplotype that encodes efficient CYP2C-substrate metabolism. The 2C19*1-2C9*2-2C8*3 haplotype was identified in all populations except African-Americans and additional novel haplotypes were identified in selected populations (for example, 2C19*2-2C9*1-2C8*4 and 2C19*4B-2C9*1-2C8*1), together indicating that both CYP2C19*17 and *2 can be linked with other CYP2C loss-of-function alleles. These results have important implications for pharmacogenomic association studies involving the CYP2C locus and are clinically relevant when administering CYP2C-substrate medications.
Personalized Medicine, 2006
Many drugs are metabolized by highly polymorphic cytochrome P450 (CYP) enzymes. Among these enzymes, members of the CYP2 family coded by the CYP2D6, CYP2C9 and CYP2C19 genes are best amenable to the precise prediction of an individual's innate capacity to metabolize drugs by DNA typing of inherited null and deficient alleles. We determined the frequency of these alleles and the prevalence of their carriers in a New England, USA, tertiary care center to assess underlying population genetic features for the practice of personalized medicine. We determined that 54, 25 and 27% are carriers of at least one deficient or null allele for the CYP2D6, CYP2C9 and CYP2C19 genes, respectively. Furthermore, 6% of individuals are carriers of two null alleles for CYP2D6 and are predicted to have no biochemical activity for this isoenzyme. These results support the implementation of DNA typing of CYP2 genes to diagnose adverse drug reactions and to prevent a substantial number of patients being prescribed drugs they cannot adequately metabolize.