PMID- 10411572
OWN - NLM
STAT- MEDLINE
DCOM- 19990818
LR  - 20211203
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 290
IP  - 2
DP  - 1999 Aug
TI  - 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.
PG  - 635-40
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 approximately 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 (approximately 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.
FAU - Ibeanu, G C
AU  - Ibeanu GC
AD  - National Institute of Environmental Health Sciences, National Institutes of
      Health, Research Triangle Park, North Carolina, USA.
FAU - Blaisdell, J
AU  - Blaisdell J
FAU - Ferguson, R J
AU  - Ferguson RJ
FAU - Ghanayem, B I
AU  - Ghanayem BI
FAU - Brosen, K
AU  - Brosen K
FAU - Benhamou, S
AU  - Benhamou S
FAU - Bouchardy, C
AU  - Bouchardy C
FAU - Wilkinson, G R
AU  - Wilkinson GR
FAU - Dayer, P
AU  - Dayer P
FAU - Goldstein, J A
AU  - Goldstein JA
LA  - eng
GR  - GM3B04/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Anticonvulsants)
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2C19 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
RN  - R420KW629U (Mephenytoin)
SB  - IM
MH  - Alleles
MH  - Anticonvulsants/*metabolism
MH  - *Aryl Hydrocarbon Hydroxylases
MH  - Cytochrome P-450 CYP2C19
MH  - Cytochrome P-450 Enzyme Inhibitors
MH  - Cytochrome P-450 Enzyme System/*genetics
MH  - Escherichia coli/genetics/metabolism
MH  - Exons
MH  - France
MH  - Genotype
MH  - Humans
MH  - Introns
MH  - Lung/enzymology
MH  - Mephenytoin/*metabolism
MH  - Mixed Function Oxygenases/antagonists & inhibitors/*genetics
MH  - Mutagenesis, Site-Directed
MH  - Phenotype
MH  - Plasmids/genetics
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Restriction Fragment Length
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Whites
EDAT- 1999/07/20 00:00
MHDA- 1999/07/20 00:01
CRDT- 1999/07/20 00:00
PHST- 1999/07/20 00:00 [pubmed]
PHST- 1999/07/20 00:01 [medline]
PHST- 1999/07/20 00:00 [entrez]
PST - ppublish
SO  - J Pharmacol Exp Ther. 1999 Aug;290(2):635-40.