TY - JOUR T1 - A Novel Transversion in the Intron 5 Donor Splice Junction of<em>CYP2C19</em> and a Sequence Polymorphism in Exon 3 Contribute to the Poor Metabolizer Phenotype for the Anticonvulsant Drug<em>S</em>-Mephenytoin JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 635 LP - 640 VL - 290 IS - 2 AU - Gordon C. Ibeanu AU - Joyce Blaisdell AU - Ronald J. Ferguson AU - Burhan I. Ghanayem AU - Kim Brøsen AU - Simone Benhamou AU - Christine Bouchardy AU - Grant R. Wilkinson AU - Pierre Dayer AU - Joyce A. Goldstein Y1 - 1999/08/01 UR - http://jpet.aspetjournals.org/content/290/2/635.abstract N2 - 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 ER -