Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity

Clin Cancer Res. 2003 Oct 1;9(12):4363-7.


Dihydropyrimidinase (DHP) is the second enzyme in the catabolism of 5-fluorouracil (5FU), and it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity. In this study, we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP. Analysis of the DHP gene showed that the patient was heterozygous for the missense mutation 833G>A (G278D) in exon 5. Heterologous expression of the mutant enzyme in Escherichia coli showed that the G278D mutation leads to a mutant DHP enzyme without residual activity. An analysis for the presence of this mutation in 96 unrelated Dutch Caucasians indicates that the allele frequency in the normal population is <0.5%. Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity.

Publication types

  • Case Reports

MeSH terms

  • Amidohydrolases / deficiency*
  • Amidohydrolases / genetics
  • Amino Acid Sequence
  • Antimetabolites, Antineoplastic / toxicity*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Carcinoma, Ductal / drug therapy
  • Carcinoma, Ductal / enzymology*
  • Chromatography, High Pressure Liquid
  • DNA Mutational Analysis
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Female
  • Fluorouracil / toxicity*
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Pharmacogenetics
  • Polymerase Chain Reaction
  • Purine-Pyrimidine Metabolism, Inborn Errors / genetics*
  • Transfection


  • Antimetabolites, Antineoplastic
  • Amidohydrolases
  • dihydropyrimidinase
  • Fluorouracil