The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans.
Article Details
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de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA
The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans.
J Biol Chem. 1994 Jun 3;269(22):15419-22.
- PubMed ID
- 8195181 [ View in PubMed]
- Abstract
The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans, with the poor metabolizer trait being inherited in an autosomal recessive fashion. There are large interracial differences in the frequency of the poor metabolizer phenotype, with Oriental populations having a 5-fold greater frequency compared to Caucasians. Impaired metabolism of mephenytoin and a number of other currently used drugs results from a defect in a cytochrome P450 enzyme recently identified as CYP2C19. Attempts over the past decade to define the molecular genetic basis of the polymorphism have, however, been unsuccessful. We now report that the principal defect in poor metabolizers is a single base pair (G-->A) mutation in exon 5 of CYP2C19, which creates an aberrant splice site. This change alters the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non-functional protein. We further demonstrate that 7/10 Caucasian and 10/17 Japanese poor metabolizers are homozygous for this defect, indicating that this is the major defect responsible for the poor metabolizer phenotype. Finally, the familial inheritance of the deficient allele was found to be concordant with that of the phenotypic trait.
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 Clopidogrel Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2 (A;A) / (A;G) - G > A (rs4244285)
Effect Directly Studied Patients with this genotype have reduced metabolism of clopidogrel resulting in reduced plasma concentrations of its active metabolite. Details Amitriptyline Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
ADR Inferred Those with the AA or AG genotype are poor metabolizers of amitriptyline Details Omeprazole Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor metabolizer, lower dose requirement, improved drug efficacy Details Clobazam Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
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 Lansoprazole Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor metabolizer, lower dose requirement, improved drug efficacy Details Mephenytoin Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor metabolizer, lower dose requirement Details Esomeprazole Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor metabolizer, lower dose requirement, improved drug efficacy Details Clopidogrel Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor drug metabolizer, lower dose requirements, higher risk for drug-drug interactions Details Proguanil Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor metabolizer, lower dose requirement Details Gliclazide Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261CYP2C19*2A Not Available - 681G>A (rs4244285)
Effect Inferred Poor drug metabolizer. Details