De Morais S M, Wilkinson G R, Blaisdell J, Meyer U A, Nakamura K, Goldstein J A
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Mol Pharmacol. 1994 Oct;46(4):594-8.
A genetic polymorphism in the metabolism of the anticonvulsant drug (S)-mephenytoin has been well documented in humans. There are marked interracial differences in the frequency of the poor metabolizer phenotype, which comprises 2-5% of Caucasian but 18-23% of Asian populations. We have recently reported that the principal genetic defect responsible for the poor metabolizer phenotype is a single-base pair mutation in exon 5 of CYP2C19 (CYP2C19m), which accounts for approximately 75-83% of the defective alleles in both Japanese and Caucasians subjects. In the present study, we have identified a new mutation (CYP2C19m2) in Japanese poor metabolizers, consisting of a guanine to adenine mutation at position 636 of exon 4 of CYP2C19, which creates a premature stop codon. Genotyping of seven Japanese poor metabolizers who were not homozygous for the previously described CYP2C19m defect (now designated CYP2C19m1) indicated that they were either homozygous for the new defect (CYP2C19m2/CYP2C19m2) or heterozygous (CYP2C19m1/CYP2C19m2) for the two defects. CYP2C19m1 accounts for 25 of 34 alleles in Japanese poor metabolizers, whereas CYP2C19m2 accounts for the remaining nine alleles. Hence, CYP2C19m1 and CYP2C19m2 explain 100% of the available Japanese poor metabolizers (34 alleles). In contrast, the CYP2C19m2 defect was not detected in nine Caucasian poor metabolizers (83% of available poor metabolizer alleles were CYP2C19m1), indicating the existence of another, as yet unidentified, mutation. Genetic testing of the families of two Japanese poor metabolizer probands showed that coinheritance of the CYP2C19m1 and CYP2C19m2 alleles was concordant with the autosomal recessive inheritance of the poor metabolizer phenotype.
抗惊厥药物（S）-美芬妥因代谢过程中的一种基因多态性在人类中已有充分记载。代谢不良者表型的频率存在显著的种族差异，在白种人中占2 - 5%，而在亚洲人群中占18 - 23%。我们最近报告称，导致代谢不良者表型的主要基因缺陷是CYP2C19第5外显子中的单碱基对突变（CYP2C19m），在日本人和白种人中，该突变约占缺陷等位基因的75 - 83%。在本研究中，我们在日本代谢不良者中鉴定出一种新的突变（CYP2C19m2），它由CYP2C19第4外显子636位的鸟嘌呤突变为腺嘌呤，从而产生一个提前终止密码子。对7名日本代谢不良者进行基因分型，这些人并非先前描述的CYP2C19m缺陷（现称为CYP2C19m1）的纯合子，结果表明他们要么是新缺陷的纯合子（CYP2C19m2/CYP2C19m2），要么是两种缺陷的杂合子（CYP2C19m1/CYP2C19m2）。在日本代谢不良者中，34个等位基因中有25个是CYP2C19m1，其余9个等位基因是CYP2C19m2。因此，CYP2C19m1和CYP2C19m2解释了所有日本代谢不良者（34个等位基因）的情况。相比之下，在9名白种人代谢不良者中未检测到CYP2C19m2缺陷（83%的可用代谢不良者等位基因是CYP2C19m1），这表明存在另一种尚未确定的突变。对两名日本代谢不良者先证者的家族进行基因检测表明，CYP2C19m1和CYP2C19m2等位基因的共同遗传与代谢不良者表型的常染色体隐性遗传一致。
