A Novel Single Nucleotide Polymorphism (SNP) of the CYP2C19 Gene in a Japanese Subject with Lowered Capacity of Mephobarbital 4′-Hydroxylation

doi:10.2133/dmpk.19.236

Drug Metabolism and Pharmacokinetics

Volume 19, Issue 3, 2004, Pages 236-238

https://doi.org/10.2133/dmpk.19.236 Get rights and content

Summary:

We sequenced all nine exons and exon-intron junctions of the cytochrome P450 2C19 (CYP2C19) gene from a Japanese subject with a lowered capacity of CYP2C19-mediated 4′-hydroxylation after an oral administration of mephobarbital. We found a novel single nucleotide polymorphism (SNP) of CYP2C19 gene as follows: SNP, 040110MoritaJ001; GENENAME: CYP2C19; ACCESSION NUMBER: NT₋030059.8; LENGTH; 25 bases; 5′-GAGGGCCTGGCCC/TGCATGGAGCTGT-3′. The SNP (168946C>T) induced an amino acid alteration (Arg442Cys) located in exon 9 close to the hemebinding region of CYP2C19, which may result in the decrease in the catalytic properties of CYP2C19. A new allele having this SNP was designated as CYP2C19*16.

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Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes
Drug Metab. Dispos.
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The CYP2 family: models, mutants and interactions
Xenobiotica
(1998)

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The cDNA is 1473 bp in length. Twenty one mutant alleles of CYP2C19 have been reported [8–14]. CYP2C19*2 to CYP2C19*8 were discovered in the subjects who demonstrated decreased ability to metabolize the prodrug, whereas CYP2C19*9 to CYP2C19*15 were reported by direct sequencing of the genomic DNA from lymphoblastoid cell lines [8] represented by Caucasians, Asians and Africans.
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150 patients taking clopidogrel drug were selected and single nucleotide polymorphism was done by PCR-RFLP techniques. With the same patients cytogenetic analysis was carried out on leukocyte cultures by karyotyping. Gene expression studies for 20 CAD patients and normal controls were done by RT-PCR techniques.
In this study of patients with coronary artery disease the frequencies of the Extreme Metabolizers, Intermediate Metabolizers in CYP2C19*2 (rs4244285) were present in 90% and 10% but no Poor Metabolizers were found in this allele. The frequencies of Extreme Metabolizer, Intermediate Metabolizer and Poor Metabolizer in CYP2C19*3 (rs4986893) were present in 41%, 50% and 9% respectively. Among 20 CAD samples, 13 of 20 (65%) showed CYP2C19 gene over expression in CAD patients and all controls showed normal expression. Among the 150 CAD patients, 145 had normal karyotype, only five patients showed change in normal karyogram carried out by leukocyte culture.
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No data regarding the metabolic phenotype of this allele were available. The allele families *13-to-*16 included one allele for each family (Blaisdell et al., 2002; Morita et al., 2004) (Table 1). No major alterations were reported identifying these families, and no data regarding the metabolic phenotypes observed in these alleles were available.
The genetics of cytochrome P450 (CYP) is a very active area of multidisciplinary research, overlapping the interest of medicine, biology and pharmacology, being the CYP enzyme system responsible for the metabolism of more than 80% of the commercially available drugs. Variations in CYP encoding genes are responsible for inter-individual differences in CYP production or function, with severe clinical consequences as therapeutic failures (TFs) and adverse drug reactions (ADRs), being ADRs worldwide primary causes of morbidity and mortality in elderly people. In fact, the prevalence of both TFs and ADRs strongly increased in the presence of multiple pharmacological treatments, a common status in subjects aging 65 years and over. The present article explored some basic concepts of human genetics that have important implications in the genetics of CYP. An attempted to transfer these basic concepts to the genetic data reported by the Home Page of The Human Cytochrome P450 (CYP) Allele Nomenclature Committee was also made, focusing on the current knowledge of CYP genetics. The status of what we know and what we need to know is the base for the clinical applications of pharmacogenetics, in which personalized drug treatments constituted the main aim, in particular in patients attending a geriatric ward.
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Mutations of the CPT II gene were analyzed according to the method of Kaneoka et al.7 The VLCAD gene contains 20 exons, and we designed primer pairs for all its exons. CYP2C19, a metabolic enzyme for phenobarbital, was analyzed according to the method of Morita et al.15 CYP2D6, a metabolic enzyme for promethazine and chlorpromazine, was analyzed using primer pairs specific to the CYP2D6 gene. The results of the genetic analysis are shown in Table 2.
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: Until January 27, 2004, the SNP reported herein has not been reported in the "Human cytochrome P450 (CYP) Allele Nomenclature Committee database (http://www.imm.ki.se/CYPalleles/) or the "JSNPs data base (http://snp.ims.u.tokyo.ac.jp/)".

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Drug Metabolism and Pharmacokinetics

Summary:

References (4)

Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes

Drug Metab. Dispos.

The CYP2 family: models, mutants and interactions

Xenobiotica

Cited by (30)

Pharmacodynamic and cytogenetic evaluation in CYP2C192 and CYP2C193 allelomorphism in South Indian population with clopidogrel therapy

Pharmacogenetics of cytochrome P450 (CYP) in the elderly

An autopsy case of rhabdomyolysis related to vegetamin and genetic analysis of the rhabdomyolysis-associated genes

Metabolism of testosterone and progesterone by cytochrome P450 2C19 allelic variants

Impact of single nucleotide polymorphisms (R132Q and W120R) on the binding affinity and metabolic activity of CYP2C19 toward some therapeutically important substrates

Cytochrome P450: Polymorphisms and roles in cancer, diabetes and atherosclerosis

SNP CommunicationA Novel Single Nucleotide Polymorphism (SNP) of the CYP2C19 Gene in a Japanese Subject with Lowered Capacity of Mephobarbital 4′-Hydroxylation

Summary:

Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes

Drug Metab. Dispos.

The CYP2 family: models, mutants and interactions

Xenobiotica

SNP Communication
A Novel Single Nucleotide Polymorphism (SNP) of the CYP2C19 Gene in a Japanese Subject with Lowered Capacity of Mephobarbital 4′-Hydroxylation