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-mephenytoin

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

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Abstrakt

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*F 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 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.

OriginalsprogEngelsk
TidsskriftJournal of Pharmacology and Experimental Therapeutics
Vol/bind290
Udgave nummer2
Sider (fra-til)635-640
Antal sider6
ISSN0022-3565
StatusUdgivet - 1. aug. 1999

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