IDENTIFICATION OF A NEW GENETIC-DEFECT RESPONSIBLE FOR THE POLYMORPHISM OF (S)-MEPHENYTOIN METABOLISM IN JAPANESE

A genetic polymorphism in the metabolism of the anticonvulsant drug (S )-mephenytoin has been well documented in humans. There are marked int erracial differences in the frequency of the poor metabolizer phenotyp e, which comprises 2-5% of Caucasian but 18-23% of Asian populations. We have recently reported: that the principal genetic defect responsib le for the poor metabolizer phenotype is a single-base pair mutation i n exon 5 of CYP2C19 (CYP2C19(m)), which accounts for similar to 75-83% of the defective alleles in both Japanese and Caucasians subjects. In the present study, we have identified a new mutation (CYP2C19(m2)) in Japanese poor metabolizers, consisting of a guanine to adenine mutati on at: position 636 of exon 4 of CYP2C19, which creates a premature st op codon. Genotyping of seven Japanese poor metabolizers who were not homozygous for the previously described CYP2C19, defect (now designate d CYP2C19(m1)) indicated that they were either homozygous for the new defect (CYP2C19(m2)/CYP2C19(m2)) or heterozygous (CYP2C19(m1)/CYP2C19( m2)) for the two defects. CYP2C19(m1),r accounts for 25 of 34 alleles in Japanese poor metabolizers, whereas CYP2C19(m2) accounts for the re maining nine alleles. Hence, CYP2C19(m1) and CYP2C19(m2) explain 100% of the available Japanese poor metabolizers (34 alleles). In contrast, the CYP2C19(m2) defect was not detected in nine Caucasian poor metabo lizers (83% of available poor metabolizer alleles were CYP2C19(m1)), i ndicating the existence of another, as yet unidentified, mutation. Gen etic testing of the families of two Japanese poor metabolizer probands showed that coinheritance of the CYP2C19(m1) and CYP2C19(m2) alleles was concordant with the autosomal recessive inheritance of the poor me tabolizer phenotype.