Medline ® Abstract for Reference 30
Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
van Kuilenburg AB, Meinsma R, Zonnenberg BA, Zoetekouw L, Baas F, Matsuda K, Tamaki N, van Gennip AH
Clin Cancer Res. 2003;9(12):4363.
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.
Academic Medical Center, University of Amsterdam, Emma Children's Hospital, and Department of Clinical Chemistry, 1100 DE Amsterdam, The Netherlands. firstname.lastname@example.org