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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Resumé

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

Fingeraftryk

Mephenytoin
Introns
Proguanil
Citalopram
RNA Splice Sites
Imipramine
Genetic Polymorphisms
Propranolol
Cytochrome P-450 Enzyme System
Proteins
Alleles
Polymerase Chain Reaction
Enzymes
Cytochrome P-450 CYP2C19

Citer dette

Ibeanu, Gordon C. ; Blaisdell, Joyce ; Ferguson, Ronald J. ; Ghanayem, Burhan I. ; Brøsen, Kim ; Benhamou, Simone ; Bouchardy, Christine ; Wilkinson, Grant R. ; Dayer, Pierre ; Goldstein, Joyce A. / 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. I: Journal of Pharmacology and Experimental Therapeutics. 1999 ; Bind 290, Nr. 2. s. 635-640.
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title = "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",
abstract = "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.",
author = "Ibeanu, {Gordon C.} and Joyce Blaisdell and Ferguson, {Ronald J.} and Ghanayem, {Burhan I.} and Kim Br{\o}sen and Simone Benhamou and Christine Bouchardy and Wilkinson, {Grant R.} and Pierre Dayer and Goldstein, {Joyce A.}",
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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. / Ibeanu, Gordon C.; Blaisdell, Joyce; Ferguson, Ronald J.; Ghanayem, Burhan I.; Brøsen, Kim; Benhamou, Simone; Bouchardy, Christine; Wilkinson, Grant R.; Dayer, Pierre; Goldstein, Joyce A.

I: Journal of Pharmacology and Experimental Therapeutics, Bind 290, Nr. 2, 01.08.1999, s. 635-640.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - 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

AU - Ibeanu, Gordon C.

AU - Blaisdell, Joyce

AU - Ferguson, Ronald J.

AU - Ghanayem, Burhan I.

AU - Brøsen, Kim

AU - Benhamou, Simone

AU - Bouchardy, Christine

AU - Wilkinson, Grant R.

AU - Dayer, Pierre

AU - Goldstein, Joyce A.

PY - 1999/8/1

Y1 - 1999/8/1

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*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.

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*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.

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M3 - Journal article

VL - 290

SP - 635

EP - 640

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -