A Novel Transversion in the Intron 5 Donor Splice Junction of CYP2C19 and a Sequence Polymorphism in Exon 3 Contribute to the Poor Metabolizer Phenotype for the Anticonvulsant Drug S-Mephenytoin

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 290; no. 2; pp. 635 - 640
• Main Authors: Ibeanu, Gordon C., Blaisdell, Joyce, Ferguson, Ronald J., Ghanayem, Burhan I., Brøsen, Kim, Benhamou, Simone, Bouchardy, Christine, Wilkinson, Grant R., Dayer, Pierre, Goldstein, Joyce A.
• Format: Journal Article
• Language: English
• Published: United States 01.08.1999
• Subjects: Alleles; Anticonvulsants - metabolism; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - genetics; Escherichia coli - genetics; Escherichia coli - metabolism; European Continental Ancestry Group; Exons; France; Genotype; Humans; Introns; Lung - enzymology; Mephenytoin - metabolism; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - genetics; Mutagenesis, Site-Directed; Phenotype; Plasmids - genetics; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0022-3565
• DOI: 10.1016/S0022-3565(24)34944-4

Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent approximately 13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.