title: Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity.
abstract: 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.
authors.affiliation: Academic Medical Center, University of Amsterdam, Emma Children's Hospital, and Department of Clinical Chemistry, 1100 DE Amsterdam, The Netherlands. a.b.vankuilenburg@acm.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Rutger
authors.initials: R
authors.lastname: Meinsma
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
authors.forename: Lida
authors.initials: L
authors.lastname: Zoetekouw
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Nanaya
authors.initials: N
authors.lastname: Tamaki
authors.forename: Albert H
authors.initials: AH
authors.lastname: van Gennip
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics; D000595:Amino Acid Sequence; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000201:enzymology*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000235:genetics*; D014162:Transfection
chemical_list: D000964:Antimetabolites, Antineoplastic; D000581:Amidohydrolases; C020047:dihydropyrimidinase; D005472:Fluorouracil