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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1996 August 1; 98(3): 610–615.
PMCID: PMC507468

Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.


Dihydropyrimidine dehydrogenase (DPD) deficiency constitutes an inborn error in pyrimidine metabolism associated with thymine-uraciluria in pediatric patients and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) treatment. The molecular basis for DPD deficiency in a British family having a cancer patient that exhibited grade IV toxicity 10 d after 5-FU treatment was analyzed. A 165-bp deletion spanning a complete exon of the DPYD gene was found in some members of the pedigree having low DPD catalytic activity. Direct sequencing of lymphocyte DNA from these subjects revealed the presence of a G to A point mutation at the 5'-splicing site consensus sequence (GT to AT) that leads to skipping of the entire exon preceding the mutation during pre-RNA transcription and processing. A PCR-based diagnostic method was developed to determine that the mutation is found in Caucasian and Asian populations. This mutation was also detected in a Dutch patient with thymine-uraciluria and completely lacking DPD activity. A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects.

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Selected References

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  • Gonzalez FJ, Fernandez-Salguero P. Diagnostic analysis, clinical importance and molecular basis of dihydropyrimidine dehydrogenase deficiency. Trends Pharmacol Sci. 1995 Oct;16(10):325–327. [PubMed]
  • Woodcock TM, Martin DS, Damin LA, Kemeny NE, Young CW. Combination clinical trials with thymidine and fluorouracil: a phase I and clinical pharmacologic evaluation. Cancer. 1980 Mar 15;45(5 Suppl):1135–1143. [PubMed]
  • Berger R, Stoker-de Vries SA, Wadman SK, Duran M, Beemer FA, de Bree PK, Weits-Binnerts JJ, Penders TJ, van der Woude JK. Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. Clin Chim Acta. 1984 Aug 31;141(2-3):227–234. [PubMed]
  • Bakkeren JA, De Abreu RA, Sengers RC, Gabreëls FJ, Maas JM, Renier WO. Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency. Clin Chim Acta. 1984 Jul 31;140(3):247–256. [PubMed]
  • Wadman SK, Berger R, Duran M, de Bree PK, Stoker-de Vries SA, Beemer FA, Weits-Binnerts JJ, Penders TJ, van der Woude JK. Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. J Inherit Metab Dis. 1985;8 (Suppl 2):113–114. [PubMed]
  • Tuchman M, Stoeckeler JS, Kiang DT, O'Dea RF, Ramnaraine ML, Mirkin BL. Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med. 1985 Jul 25;313(4):245–249. [PubMed]
  • Diasio RB, Beavers TL, Carpenter JT. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. J Clin Invest. 1988 Jan;81(1):47–51. [PMC free article] [PubMed]
  • Harris BE, Carpenter JT, Diasio RB. Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome. Cancer. 1991 Aug 1;68(3):499–501. [PubMed]
  • Houyau P, Gay C, Chatelut E, Canal P, Roché H, Milano G. Severe fluorouracil toxicity in a patient with dihydropyrimidine dehydrogenase deficiency. J Natl Cancer Inst. 1993 Oct 6;85(19):1602–1603. [PubMed]
  • Meinsma R, Fernandez-Salguero P, Van Kuilenburg AB, Van Gennip AH, Gonzalez FJ. Human polymorphism in drug metabolism: mutation in the dihydropyrimidine dehydrogenase gene results in exon skipping and thymine uracilurea. DNA Cell Biol. 1995 Jan;14(1):1–6. [PubMed]
  • Milano G, Etienne MC. Potential importance of dihydropyrimidine dehydrogenase (DPD) in cancer chemotherapy. Pharmacogenetics. 1994 Dec;4(6):301–306. [PubMed]
  • Milano G, Etienne MC. Dihydropyrimidine dehydrogenase (DPD) and clinical pharmacology of 5-fluorouracil (review). Anticancer Res. 1994 Nov-Dec;14(6A):2295–2297. [PubMed]
  • Yokota H, Fernandez-Salguero P, Furuya H, Lin K, McBride OW, Podschun B, Schnackerz KD, Gonzalez FJ. cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria. J Biol Chem. 1994 Sep 16;269(37):23192–23196. [PubMed]
  • McMurrough J, McLeod HL. Analysis of the dihydropyrimidine dehydrogenase polymorphism in a British population. Br J Clin Pharmacol. 1996 May;41(5):425–427. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Fernandez-Salguero P, Hoffman SM, Cholerton S, Mohrenweiser H, Raunio H, Rautio A, Pelkonen O, Huang JD, Evans WE, Idle JR, et al. A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet. 1995 Sep;57(3):651–660. [PubMed]
  • Marvit J, DiLella AG, Brayton K, Ledley FD, Robson KJ, Woo SL. GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria. Nucleic Acids Res. 1987 Jul 24;15(14):5613–5628. [PMC free article] [PubMed]
  • Cole WG, Chiodo AA, Lamande SR, Janeczko R, Ramirez F, Dahl HH, Chan D, Bateman JF. A base substitution at a splice site in the COL3A1 gene causes exon skipping and generates abnormal type III procollagen in a patient with Ehlers-Danlos syndrome type IV. J Biol Chem. 1990 Oct 5;265(28):17070–17077. [PubMed]
  • Steingrimsdottir H, Rowley G, Dorado G, Cole J, Lehmann AR. Mutations which alter splicing in the human hypoxanthine-guanine phosphoribosyltransferase gene. Nucleic Acids Res. 1992 Mar 25;20(6):1201–1208. [PMC free article] [PubMed]
  • Robberson BL, Cote GJ, Berget SM. Exon definition may facilitate splice site selection in RNAs with multiple exons. Mol Cell Biol. 1990 Jan;10(1):84–94. [PMC free article] [PubMed]
  • Berget SM. Exon recognition in vertebrate splicing. J Biol Chem. 1995 Feb 10;270(6):2411–2414. [PubMed]
  • Fernandez-Salguero P, Gonzalez FJ, Etienne MC, Milano G, Kimura S. Correlation between catalytic activity and protein content for the polymorphically expressed dihydropyrimidine dehydrogenase in human lymphocytes. Biochem Pharmacol. 1995 Sep 28;50(7):1015–1020. [PubMed]
  • Lu Z, Zhang R, Diasio RB. Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993 Nov 15;53(22):5433–5438. [PubMed]
  • Lu Z, Zhang R, Diasio RB. Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy. Clin Pharmacol Ther. 1995 Nov;58(5):512–522. [PubMed]
  • Fleming RA, Milano G, Thyss A, Etienne MC, Renée N, Schneider M, Demard F. Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res. 1992 May 15;52(10):2899–2902. [PubMed]

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