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 journalArticle

25 Citations (Scopus)

Abstract

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
Volume18
Issue number1
DOIs
StatePublished - Jan 2008

Fingerprint

Uracil
Dihydrouracil Dehydrogenase (NADP)
Breath Tests
Dihydropyrimidine Dehydrogenase Deficiency
Enzymes
Genes
dihydropyrimidinase
Fluorouracil
Mutation
Digestion
Healthy Volunteers
High Pressure Liquid Chromatography
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Pharmacology

Cite this

Genetic regulation of β-ureidopropionase and its possible implication in altered uracil catabolism. / Thomas, Holly R.; Ezzeldin, Hany H.; Guarcello, Vincenzo; Mattison, Lori K.; Fridley, Brooke L.; Diasio, Robert B.

In: Pharmacogenetics and Genomics, Vol. 18, No. 1, 01.2008, p. 25-35.

Research output: Contribution to journalArticle

Thomas, Holly R. ; Ezzeldin, Hany H. ; Guarcello, Vincenzo ; Mattison, Lori K. ; Fridley, Brooke L. ; Diasio, Robert B. / Genetic regulation of β-ureidopropionase and its possible implication in altered uracil catabolism. In: Pharmacogenetics and Genomics. 2008 ; Vol. 18, No. 1. pp. 25-35.
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AB - 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.

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