Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.
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De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA
Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.
Mol Pharmacol. 1994 Oct;46(4):594-8.
- PubMed ID
- 7969038 [ View in PubMed]
- Abstract
A genetic polymorphism in the metabolism of the anticonvulsant drug (S)-mephenytoin has been well documented in humans. There are marked interracial differences in the frequency of the poor metabolizer phenotype, which comprises 2-5% of Caucasian but 18-23% of Asian populations. We have recently reported that the principal genetic defect responsible for the poor metabolizer phenotype is a single-base pair mutation in exon 5 of CYP2C19 (CYP2C19m), which accounts for approximately 75-83% of the defective alleles in both Japanese and Caucasians subjects. In the present study, we have identified a new mutation (CYP2C19m2) in Japanese poor metabolizers, consisting of a guanine to adenine mutation at position 636 of exon 4 of CYP2C19, which creates a premature stop codon. Genotyping of seven Japanese poor metabolizers who were not homozygous for the previously described CYP2C19m defect (now designated CYP2C19m1) indicated that they were either homozygous for the new defect (CYP2C19m2/CYP2C19m2) or heterozygous (CYP2C19m1/CYP2C19m2) for the two defects. CYP2C19m1 accounts for 25 of 34 alleles in Japanese poor metabolizers, whereas CYP2C19m2 accounts for the remaining nine alleles. Hence, CYP2C19m1 and CYP2C19m2 explain 100% of the available Japanese poor metabolizers (34 alleles). In contrast, the CYP2C19m2 defect was not detected in nine Caucasian poor metabolizers (83% of available poor metabolizer alleles were CYP2C19m1), indicating the existence of another, as yet unidentified, mutation. Genetic testing of the families of two Japanese poor metabolizer probands showed that coinheritance of the CYP2C19m1 and CYP2C19m2 alleles was concordant with the autosomal recessive inheritance of the poor metabolizer phenotype.
DrugBank Data that Cites this Article
- Polypeptides
Name UniProt ID Cytochrome P450 2C19 P33261 Details - Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Mephenytoin Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*3 (A;A) - A Allele, homozygote (rs4986893)
Effect Directly Studied Patients with this genotype have reduced metabolism of mephenytoin. Details Amitriptyline Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*3 Not Available - 636G>A (rs4986893)
ADR Inferred Those with the AA or AG genotype are poor metabolizers of amitriptyline Details Clobazam Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*3 Not Available - 636G>A (rs4986893)
ADR Inferred Clobazem is metabolized into N-desmethylclobazem (NCLB) mostly by CYP3A4. NCLB is primarily metabolized by 2C19. Those with one 2C19*2 allele mutation (1*/2*) are intermediate metabolizers of NCLB. Those with two (2*/2*) mutations will metabolize NCLB poorly in comparisone to extensive metabolizers (1*/1*). Levels of NCLB can be five times higher in poor metabolizers, and two times higher in intermediate metabolizers as compared to individuals who are extensive metabolizers. The safety and efficacy of clobazem may be affected by polymorphic expression of CYP2C19*2. Details Clopidogrel Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*3 Not Available - 636G>A (rs4986893)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions Details