Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity

André B. P. van Kuilenburg, Rutger Meinsma, Bernard A. Zonnenberg, Lida Zoetekouw, Frank Baas, Koichi Matsuda, Nanaya Tamaki, Albert H. van Gennip

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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
Original languageEnglish
Pages (from-to)4363-4367
JournalClinical cancer research
Issue number12
Publication statusPublished - 2003

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