PT - JOURNAL ARTICLE AU - Ronald J. Ferguson AU - Sonia M.F. De Morais AU - Simone Benhamou AU - Christine Bouchardy AU - Joyce Blaisdell AU - Gordon Ibeanu AU - Grant R. Wilkinson AU - Troy C. Sarich AU - James M. Wright AU - Pierre Dayer AU - Joyce A. Goldstein TI - A New Genetic Defect in Human <em>CYP2C19</em>: Mutation of the Initiation Codon Is Responsible for Poor Metabolism of <em>S</em>-Mephenytoin DP - 1998 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 356--361 VI - 284 IP - 1 4099 - http://jpet.aspetjournals.org/content/284/1/356.short 4100 - http://jpet.aspetjournals.org/content/284/1/356.full SO - J Pharmacol Exp Ther1998 Jan 01; 284 AB - The 4′-hydroxylation of the S-enantiomer of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism shows marked interracial heterogeneity, with the poor metabolizer (PM) phenotype representing 2 to 5% of Caucasian and 13 to 23% of Asian populations. Two defective CYP2C19alleles, CYP2C19*2 and CYP2C19*3, have been described which account for ∼87% of Caucasian and &gt;99% of Oriental PM alleles. The present study identifies a new allele (CYP2C19*4) in Caucasian PMs which contains an A → G mutation in the initiation codon. A new polymerase chain reaction-restriction fragment length polymorphism genotyping test was developed, and the incidence of this allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. One of nine putative PMs was heterozygous forCYP2C19*2/CYP2C19*4, which suggests thatCYP2C19*4 represents a defective allele. Six of the seven remaining putative PMs available for genotyping were explained byCYP2C19*2. The frequency of the CYP2C19*4 allele in Caucasians was 0.6%. An additional Caucasian PM from a separate study was also heterozygous for CYP2C19*2 andCYP2C19*4. To verify that CYP2C19*4 represented a defective CYP2C19 allele, the initiation codon of the normal CYP2C19*1 cDNA was mutated to a GTG, and both cDNAs were expressed in yeast. Recombinant CYP2C19 protein was detected by Western blot analysis of colonies transformed with CYP2C19*1 cDNA, but not in those transformed with CYP2C19*4 cDNA. The two cDNAs were also used in an in vitro coupled transcription/translation assay. CYP2C19 protein was translated only from the CYP2C19*1 allele. These data indicate that CYP2C19*4 represents a new PM allele. The American Society for Pharmacology and Experimental Therapeutics