Genetic analysis of the cytochrome P‐450IIC18 (CYP2C18) gene and a novel member of the CYP2C subfamily

Tsuneoka, Yutaka; Matsuo, Yosuke; Okuyama, Eisaku; Watanabe, Yasuhiro; Ichikawa, Yoshiyuki

doi:10.1016/0014-5793(96)00329-8

Cited by 9 publications

(4 citation statements)

References 11 publications

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“…CYP2C8 also plays a direct role in the metabolism of some important therapeutic drugs, including paclitaxel, amodiaquine, troglitazone, amiodarone, verapamil, cerivastatin, and fluvastatin. 10 Although variant CYP2C18 alleles have been reported, 11–12 CYP2C18 expression is not consistent with a major role in hepatic drug metabolism and specific CYP2C18-substrates have yet to be clearly identified. 3 Both common and rare CYP2C19 , CYP2C9 , and CYP2C8 variant alleles have been identified in different populations, which are catalogued by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee.…”

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confidence: 99%

Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes

et al. 2012

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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 ~0.30–0.41; however, the CYP2C8 frequencies were much lower (~0.04–0.13). After incorporating previously reported CYP2C9 genotyping results from these populations (36 total CYP2C variants), 16 multi-ethnic CYP2C haplotypes were inferred with frequencies >0.5%. 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 (e.g., 2C19*2-2C9*1-2C8*4, 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.

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Section: Introductionmentioning

confidence: 99%

Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes

et al. 2012

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“…The consequences of these polymorphisms have not been examined clinically. Polymorphisms of CYP2C18 have also been described [14, 15], but CYP2C18 protein has not yet been found in detectable amounts in any tissues. Until this protein is shown to have some function in vivo , the polymorphisms in this enzyme are primarily of intellectual interest.…”

Section: Introductionmentioning

confidence: 99%

Clinical relevance of genetic polymorphisms in the human CYP2C subfamily

Goldstein

2001

Brit J Clinical Pharma

576

406

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The human CYP2Cs are an important subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs. There are four members of the subfamily, CYP2C8, CYP2C9, CYP2C19, and CYP2C18. Of these CYP2C8, CYP2C9, and CYP2C19 are of clinical importance. The CYP2Cs also metabolize some endogenous compounds such as arachidonic acid. Each member of this subfamily has been found to be genetically polymorphic. The most well-known of these polymorphisms is in CYP2C19. Poor metabolizers (PMs) of CYP2C19 represent approximately 3±5% of Caucasians, a similar percentage of African-Americans and 12±100% of Asian groups. The polymorphism affects metabolism of the anticonvulsant agent mephenytoin, proton pump inhibitors such as omeprazole, the anxiolytic agent diazepam, certain antidepressants, and the antimalarial drug proguanil. Toxic effects can occur in PMs exposed to diazepam, and the ef®cacy of some proton pump inhibitors may be greater in PMs than EMs at low doses of these drugs. A number of mutant alleles exist that can be detected by genetic testing. CYP2C9 metabolizes a wide variety of drugs including the anticoagulant warfarin, antidiabetic agents such as tolbutamide, anticonvulsants such as phenytoin, and nonsteroidal anti-in¯ammatory drugs. The incidence of functional polymorphisms is much lower, estimated to be 1/250 in Caucasians and lower in Asians. However, the clinical consequences of these rarer polymorphisms can be severe. Severe and life-threatening bleeding episodes have been reported in CYP2C9 PMs exposed to warfarin. Phenytoin has been reported to cause severe toxicity in PMs. New polymorphisms have been discovered in CYP2C8, which metabolizes taxol (paclitaxel). Genetic testing is available for all of the known CYP2C variant alleles.

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“…This anomaly yielded a truncated 67-amino-acid CYP2C18 lacking a haem-binding region. Tsuneoka et al (1996) discovered a single nucleotide change (T to C) at position À478 of the 5 Hanking region (CYP2C18m2). Mamiya et al (1998) recently reported that, in a Japanese population, genotypes of CYP2C18m1 and CYP2C18m2 were completely coincident with those of CYP2C19*3 and CYP2C19*2, respectively.…”

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confidence: 99%

“…CYP2C19*1 and the mutated alleles, CYP2C19*2 and CYP2C19*3, were identi®ed by PCR ampli®cation with speci®c primers and by the restriction fragment length polymorphism (RFLP) procedure described by de Morais et al (1994a, b). CYP2C18wt and the mutated alleles, CYP2C18m1 and CYP2C18m2, were identi®ed by PCR ampli®cation using speci®c primers and by the RFLP methods described by Komai et al (1996) and by Tsuneoka et al (1996), respectively.…”

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confidence: 99%

Rapid Detection of CYP2C18 Genotypes by Real-time Fluorescence Polymerase Chain Reaction

Mizugaki

Hiratsuka

Agatsuma

et al. 2000

Journal of Pharmacy and Pharmacology

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In man, CYP2C19, a liver enzyme, plays an important role in the metabolism of several drugs. Mutation of the CYP2C19 gene results in a poor metaboliser phenotype. S-Mephenytoin hydroxylation genetic polymorphism is due to two mutations of the CYP2C19 gene, namely CYP2C19*2, located in exon 5, and CYP2C19*3, located in exon 4. CYP2C18 is also polymorphically expressed. The mutant alleles of this enzyme are CYP2C18m1, located in exon 2 and CYP2C18m2, located in the 5'-flanking region. We have developed an allele-specific TaqMan polymerase chain reaction (PCR) assay with which to detect CYP2C18 mutant alleles. This assay combines hybridization of the TaqMan probe and allele-specific amplification primers to the target DNA. The TaqMan probe is labelled with 6-carboxyfluorescein at the 5' end and 6-carboxytetramethylrhodamine together with a phosphate at the 3' end. Genotypes are separated according to the different threshold cycles of the wild type and mutant primers. We applied this procedure to DNA extracted from the blood or saliva of 144 healthy Japanese volunteers. The wt/wt, wt/m1, wt/m2, m1/m1, m1/m2 and m2/m2 genotypes of the CYP2C18 alleles detected by the assay were consistent with the results obtained from restriction enzyme cleavage. In accordance with a previous report, the genotypes of CYP2C18m1 and CYP2C18m2 coincided with those of CYP2C19*3 and CYP2C19*2, respectively. Therefore, detection of CYP2C18 mutant alleles also allows that of CYP2C19 mutant alleles. Among 19 poor metabolisers, eight showed the homozygous CYP2C19*2/CYP2C19*2, two the homozygous CYP2C19*3/CYP2C19*3 and nine the compound heterozygous CYP2C19*2/CYP2C19*3 genotype. We found the allele-specific TaqMan PCR assay rapid, simple and cost-effective, as well as suitable for high-throughput applications in a routine laboratory. This assay allows the fast and reliable detection of inherited disorders that might influence diagnosis and treatment.

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Genetic analysis of the cytochrome P‐450IIC18 (CYP2C18) gene and a novel member of the CYP2C subfamily

Cited by 9 publications

References 11 publications

Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes

Multi-ethnic distribution of clinically relevant CYP2C genotypes and haplotypes

Clinical relevance of genetic polymorphisms in the human CYP2C subfamily

Rapid Detection of CYP2C18 Genotypes by Real-time Fluorescence Polymerase Chain Reaction

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