PT  - JOURNAL ARTICLE
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
TI  - 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
DP  - 1999 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 635--640
VI  - 290
IP  - 2
4099  - http://jpet.aspetjournals.org/content/290/2/635.short
4100  - http://jpet.aspetjournals.org/content/290/2/635.full
SO  - J Pharmacol Exp Ther1999 Aug 01; 290
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