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