Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanesepopulation in relation to toxicity to 5-fluorouracil

5-Fluorouracil (5FU) is most commonly used in chemotherapy for human malign ancy, Over 80% of administered 5FU is metabolically degraded by dihydropyri midine dehydrogenase (DPD), a primary and rate-limiting enzyme in the 5FU m etabolic pathway. A DPD-deficient phenotype among cancer patients, which ha s posed a serious problem in 5FU-based chemotherapy, was reported to be in part ascribed to germline mutations in dihydropyrimidine dehydrogenase (DPY D) gene. Therefore, we for the first time examined the frequencies and type s of germline mutations in the DPYD gene among a total of 107 Japanese canc er patients and healthy volunteers. Of 214 alleles examined among them, 181 alleles were of the same type, which was assigned as wild type; 21 alleles revealed a nucleotide substitution resulting in silent mutation; and the r emaining 12 alleles showed five types of nucleotide deletion or substitutio ns resulting in one frameshift and four missense mutations. Three of them. A74G, 812delT and L572V, were novel mutations. None of the study subjects s howed homozygous frameshift or missense mutated alleles, We also studied th e association between toxic response to 5FU and heterozygous frame shift or missense mutation of the DPYD gene among eight cancer patients who had rec eived 5FU-based chemotherapy. These patients did not show any adverse effec ts higher than grade 3, suggesting that heterozygotes are not associated wi th increased toxicity to 5FU. Our results indicate that a very small percen tage, about 0.2%, of the Japanese population seems to carry homozygous muta tions in DPYD gene, mutations which possibly indicate genetically increased toxicity of 5FU-based chemotherapy.