title: Identification of novel mutations in the dihydropyrimidine dehydrogenase gene in a Japanese patient with 5-fluorouracil toxicity.
abstract: 5-Fluorouracil (5-FU) is used widely in the treatment of several common neoplasms. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. Several recent studies have described a pharmacogenetic disorder in which cancer patients with decreased DPD activity develop life-threatening toxicity following exposure to 5-FU. We reported recently the first Japanese case of decreased DPD activity accompanied by severe 5-FU toxicity. The present study describes the results of molecular analysis of this patient and her family, in which three novel mutations (Arg21Gln, Val335Leu, and Glu386Ter) of the gene coding for DPD were identified. 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 Val335Leu and Glu386Ter led to mutant DPD protein with significant loss of enzymatic 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 deficiency accompanied by severe 5-FU toxicity in a Japanese patient.
authors.affiliation: Department of Pediatrics, Nagoya City University Medical School, Nagoya, Japan. kouwaki@med.nagoya-cu.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Kouwaki
authors.forename: N
authors.initials: N
authors.lastname: Hamajima
authors.forename: S
authors.initials: S
authors.lastname: Sumi
authors.forename: M
authors.initials: M
authors.lastname: Nonaka
authors.forename: M
authors.initials: M
authors.lastname: Sasaki
authors.forename: K
authors.initials: K
authors.lastname: Dobashi
authors.forename: K
authors.initials: K
authors.lastname: Kidouchi
authors.forename: H
authors.initials: H
authors.lastname: Togari
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002384:Catalysis; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007564:Japan; D008875:Middle Aged; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000652:urine; D017422:Sequence Analysis, DNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D011743:Pyrimidines; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil