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Dihydropyrimidinase Deficiency and Severe 5-Fluorouracil Toxicity

Academic Medical Center, University of Amsterdam, Emma Children’s Hospital, and Departments of Clinical Chemistry and Neurogenetics, 1100 DE Amsterdam, the Netherlands [A. B. P. v. K., R. M., L. Z., F. B., A. H. v. G.]; University Medical Center Utrecht, Department of Medical Oncology, 3508 GA Utrecht, the Netherlands [B. A. Z.]; and Kobe Gakuin University Igawadani-cho, Kobe, Japan [K. M., N. T.]

Dihydropyrimidinase (DHP) is the second enzyme in the catabolism of 5-fluorouracil (5FU), and it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity. In this study, we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP. Analysis of the DHP gene showed that the patient was heterozygous for the missense mutation 833G>A (G278D) in exon 5. Heterologous expression of the mutant enzyme in Escherichia coli showed that the G278D mutation leads to a mutant DHP enzyme without residual activity. An analysis for the presence of this mutation in 96 unrelated Dutch Caucasians indicates that the allele frequency in the normal population is <0.5%. Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity.

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