Genetic regulation of β-ureidopropionase 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

27 Scopus citations


OBJECTIVE: Approximately 30-40% of grade III-IV toxicity to 5-FU has been associated with partial or profound deficiency in dihydropyrimidine dehydrogenase (DPD), the first of three enzymes in the catabolic pathway of fluoropyrimidines. There remains, however, a subset of patients presenting with 5-FU-associated toxicity despite normal DPD activity, suggesting possible deficiencies in enzymes downstream of DPD: dihydropyrimidinase (DHP), encoded by the DPYS gene, and/or β-ureidopropionase (BUP-1), encoded by the UPB1 gene. Previously, we reported the identification of inactivating mutations in the DPYS gene that could potentially alter the uracil catabolic pathway in healthy individuals with normal DPD enzyme activity. This study investigates the possible role of UPB1 genetic variations in the regulation of the uracil catabolic pathway in individuals presenting with a deficient uracil breath test (C-UraBT) despite normal DPD enzyme activity. METHODS: This study included 219 healthy asymptomatic volunteers with known DPD enzyme activity and [2-C]-uracil breath test (UraBT). All samples were genotyped for sequence variations in the UPB1 gene using denaturing high performance liquid chromatography (DHPLC) and Surveyor enzyme digestion with confirmation of detected sequence variants by direct sequencing. RESULTS: Seven novel and six previously reported sequence variations were identified, including one nonconservative mutation, which demonstrated 97.3% reduction in BUP-1 activity when expressed in the RKO cell line. CONCLUSION: Data presented in this study demonstrate that alterations of uracil catabolism are not limited to DPD and/or DHP deficiency and that inactivating mutations in the UPB1 gene might impair uracil catabolism.

Original languageEnglish (US)
Pages (from-to)25-35
Number of pages11
JournalPharmacogenetics and genomics
Issue number1
StatePublished - Jan 2008


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

ASJC Scopus subject areas

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


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