RT Journal Article SR Electronic T1 A Novel Transversion in the Intron 5 Donor Splice Junction ofCYP2C19 and a Sequence Polymorphism in Exon 3 Contribute to the Poor Metabolizer Phenotype for the Anticonvulsant DrugS-Mephenytoin JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 635 OP 640 VO 290 IS 2 A1 Gordon C. Ibeanu A1 Joyce Blaisdell A1 Ronald J. Ferguson A1 Burhan I. Ghanayem A1 Kim Brøsen A1 Simone Benhamou A1 Christine Bouchardy A1 Grant R. Wilkinson A1 Pierre Dayer A1 Joyce A. Goldstein YR 1999 UL http://jpet.aspetjournals.org/content/290/2/635.abstract AB 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 ∼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 (∼90% and 70%) reduction in the metabolism ofS-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. The American Society for Pharmacology and Experimental Therapeutics