Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity

5-Fluorouracil (5-FU) is used widely in the treatment of several common neo plasms. Dihydropyrimidine dehydro genase (DPD) is the initial and rate-limi ting enzyme in the catabolism of 5-FU, Several recent studies have describe d a pharmacogenetic disorder in which cancer patients with decreased DPD ac tivity develop life-threatening toxicity following exposure to 5-FU. We rep orted recently the first Japanese case of decreased DPD activity accompanie d by severe 5-FU toxicity. The present study describes the results of molec ular analysis of this patient and her family, in which three novel mutation s (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were iden tified. We also revealed that Arg21Gln and Glu386Ter are on the same allele and that Val335Leu is on the other allele, on the basis of analysis of the family genome. Expression analysis in Escherichia coli showed that Val335L eu and Glu386Ter led to mutant DPD protein with significant loss of enzymat ic activity and no activity, respectively, The Arg21Gln mutation, however, resulted in no decrease in enzymatic activity compared with the wild type. The present data represent the first molecular genetic analysis of DPD defi ciency accompanied by severe 5-FU toxicity in a Japanese patient.