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dihydropyrimidine dehydrogenase

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Target not currently curated in GtoImmuPdb

Target id: 3102

Nomenclature: dihydropyrimidine dehydrogenase

Family: Nucleotide turnover

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1025 1p21.3 DPYD dihydropyrimidine dehydrogenase
Mouse - 1025 3 G1 Dpyd dihydropyrimidine dehydrogenase
Rat - 1025 2q41 Dpyd dihydropyrimidine dehydrogenase
Previous and Unofficial Names Click here for help
DHPDHase | dihydropyrimidine dehydrogenase [NADP(+)] | DPD
Database Links Click here for help
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ChEMBL Target
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Enzyme Reaction Click here for help
EC Number: 1.3.1.2

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Inhibitors
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Ligand Sp. Action Value Parameter Reference
RO0094889 Small molecule or natural product Hs Inhibition - - 4
[4]
Gene Expression and Pathophysiology Comments
Genetic deficiency of dihydropyrimidine dehydrogenase activity causes elevated levels of thymine and uracil in the urine (thymine-uraciluria) [1,8-9]. In patients receiving 5-fluorouracil-based chemotherapy DPD deficiency is a pharmacogenetic factor that can dramatically increase the risk of drug-induced toxicity [3,5-6].
General Comments
Dihydropyrimidine dehydrogenase (DPD) is required for the first and rate-limiting step of pyrimidine catabolism [7]. In addition to degrading pyrimidines, it also breaks down pyrimidine-based 5-fluorouracil which is the active metabolite of several chemotherapeutic prodrugs (capecitabine, floxuridine, tegafur). DPD inhibitors have been investigated for their potential to enhance 5-fluorouracil levels in the vicinity of tumours being treated with 5-fluorouracil-producing prodrugs [2,4].

References

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1. Bakkeren JA, De Abreu RA, Sengers RC, Gabreëls FJ, Maas JM, Renier WO. (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta, 140 (3): 247-56. [PMID:6467612]

2. Bellibas SE, Patel I, Chamorey E, Brivet B, Bush ED, Kircher C, Nave S, Banken L, Renée N, Milano G. (2004) Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889. Clin Cancer Res, 10 (7): 2327-35. [PMID:15073108]

3. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M. (2013) Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther, 94 (6): 640-5. [PMID:23988873]

4. Hattori K, Kohchi Y, Oikawa N, Suda H, Ura M, Ishikawa T, Miwa M, Endoh M, Eda H, Tanimura H et al.. (2003) Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine. Bioorg Med Chem Lett, 13 (5): 867-72. [PMID:12617910]

5. Omura K. (2003) Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5-FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines. Int J Clin Oncol, 8 (3): 132-8. [PMID:12851836]

6. Schneider HB, Becker H. (2003) Impact of dihydropyrimidine dehydrogenase on 5-fluorouracil treatment in cancer patients. Eur J Med Res, 8 (5): 226-8. [PMID:12844478]

7. Van Kuilenburg AB, Vreken P, Abeling NG, Bakker HD, Meinsma R, Van Lenthe H, De Abreu RA, Smeitink JA, Kayserili H, Apak MY et al.. (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet, 104 (1): 1-9. [PMID:10071185]

8. Vreken P, Van Kuilenburg AB, Meinsma R, Smit GP, Bakker HD, De Abreu RA, van Gennip AH. (1996) A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis, 19 (5): 645-54. [PMID:8892022]

9. Vreken P, Van Kuilenburg AB, Meinsma R, van Gennip AH. (1997) Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W. Hum Genet, 101 (3): 333-8. [PMID:9439663]

How to cite this page

Nucleotide turnover: dihydropyrimidine dehydrogenase. Last modified on 08/07/2020. Accessed on 24/10/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3102.