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Vol. 290, Issue 2, 635-640, August 1999

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-Mephenytoin1

Gordon C. Ibeanu, Joyce Blaisdell, Ronald J. Ferguson, Burhan I. Ghanayem, Kim Brøsen, Simone Benhamou, Christine Bouchardy, Grant R. Wilkinson, Pierre Dayer and Joyce A. Goldstein

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (G.C.I., J.B., B.I.G, J.A.G.); University of Florida, Gainesville, Florida (R.J.F.); Department of Clinical Pharmacology, Odense University, Odense, Denmark (K.B.); Institut National de la Santé et de la Recherche Médicale U351, Villejuif, France (S.B.); Geneva Cancer Registry, Geneva, Switzerland (C.B.); Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee (G.R.W.); and Geneva University Hospital, Geneva, Switzerland (P.D.)

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 right-arrow 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 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.

0022-3565/99/2902-0635$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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