Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism

Holly R. Thomas, Hany H. Ezzeldin, Vincenzo Guarcello, Lori K. Mattison, Brooke L. Fridley, Robert B. Diasio

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


OBJECTIVE: Dihydropyrimidine dehydrogenase (DPD) deficiency accounts for approximately 43% of grade 3-4 toxicity to 5-fluorouracil. There, however, remain a number of patients presenting with 5-fluorouracil-associated toxicity despite normal DPD enzyme activity, suggesting possible deficiencies in dihydropyrimidinase (DHP), encoded by the DPYS gene, and/or β- ureidopropionase (BUP-1), encoded by the UPB1 gene. This study investigates the role of DPYS sequence variations in individuals with unexplained molecular basis of altered uracil catabolism. METHODS: This study included 219 asymptomatic healthy volunteers with known DPD enzyme activity and [2-C]-uracil breath test (UraBT) profiles. All samples were genotyped for sequence variations in the DPYS gene using denaturing high-performance liquid chromatography (DHPLC) and Surveyor enzyme digestion with confirmation by direct sequencing. Site-directed mutagenesis and expression analysis were performed to determine the effect of the identified nonconservative mutations on DHP enzyme activity. RESULTS: Seven previously reported and 11 novel sequence variations were identified, including three nonconservative mutations; two of which (L7V and 1635delC) demonstrated decreased DHP activity when expressed in the RKO cell line (P=0.25). The P values were not significant due to the small sample size (n=3); however, a modified [2-C]-uracil breath test, the C-dihydrouracil breath test, was administered to four volunteers to confirm that the 1635delC mutation does in fact reduce in-vivo DHP activity. CONCLUSION: Data presented in this study demonstrate that alterations of uracil catabolism are not limited to DPD deficiency, and that inactivating mutations in DHP might impair uracil catabolism in cases of normal DPD activity.

Original languageEnglish (US)
Pages (from-to)973-987
Number of pages15
JournalPharmacogenetics and genomics
Issue number11
StatePublished - Nov 2007


  • C-dihydrouracil breath test
  • C-uracil breath test
  • Denaturing high-performance liquid chromatography
  • Dihydropyrimidinase
  • Uracil catabolism

ASJC Scopus subject areas

  • Genetics(clinical)
  • General Pharmacology, Toxicology and Pharmaceutics
  • Genetics
  • Molecular Medicine
  • Molecular Biology


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