PMID- 10022751
OWN - NLM
STAT- MEDLINE
DCOM- 19990413
LR  - 20211203
IS  - 0960-314X (Print)
IS  - 0960-314X (Linking)
VI  - 8
IP  - 2
DP  - 1998 Apr
TI  - An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor 
      metabolizer phenotype in Caucasians.
PG  - 129-35
AB  - The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic
      polymorphism in humans. This polymorphism exhibits marked racial heterogeneity,
      with the poor metabolizer PM phenotype representing 13-23% of oriental
      populations, but only 2-5% of Caucasian populations. Two defective CYP2C19
      alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more
      than 99% of Oriental poor metabolizer alleles but only approximately 87% of
      Caucasian poor metabolizer alleles. Therefore, additional defects presumably
      contribute to the poor metabolizer in Caucasians. Recent studies have found a
      third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor
      metabolizer alleles. A fourth rare mutation (CYP2C19*5A)
      (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution 
      in the heme-binding region has been reported in a single Chinese poor metaboliser
      outlier belonging to the Bai ethnic group. The present study identifies a second 
      variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp
      in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles 
      is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (<
      0.9%). However, these alleles contribute to the poor metabolizer phenotype in
      both ethnic groups and increases the sensitivity of the genetic tests for
      identifying defective alleles to approximately 100% in Chinese poor metabolizers 
      and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to
      Trp mutation in the heme-binding region essentially abolishes activity of
      recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent 
      with the conclusion that CYP2C19*5 represents poor metabolizer alleles.
FAU - Ibeanu, G C
AU  - Ibeanu GC
AD  - NIEHS, Research Triangle Park, NC 27709, USA.
FAU - Blaisdell, J
AU  - Blaisdell J
FAU - Ghanayem, B I
AU  - Ghanayem BI
FAU - Beyeler, C
AU  - Beyeler C
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 - Daly, A K
AU  - Daly AK
FAU - Goldstein, J A
AU  - Goldstein JA
LA  - eng
PT  - Journal Article
PL  - England
TA  - Pharmacogenetics
JT  - Pharmacogenetics
JID - 9211735
RN  - 0 (Anticonvulsants)
RN  - 0 (DNA Primers)
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  - Amino Acid Substitution
MH  - Anticonvulsants/*metabolism
MH  - *Aryl Hydrocarbon Hydroxylases
MH  - Base Sequence
MH  - Cytochrome P-450 CYP2C19
MH  - Cytochrome P-450 Enzyme System/chemistry/*genetics
MH  - DNA Primers
MH  - Humans
MH  - Mephenytoin/*metabolism
MH  - Mixed Function Oxygenases/chemistry/*genetics
MH  - Phenotype
MH  - Whites/*genetics
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1097/00008571-199804000-00006 [doi]
PST - ppublish
SO  - Pharmacogenetics. 1998 Apr;8(2):129-35. doi: 10.1097/00008571-199804000-00006.