title: Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0.01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10.0 +/- 7.6 versus 19.1 +/- 15.3 days, P < 0.05). In patients suffering from severe 5FU-associated toxicity, 11 mutations have been identified in DPYD, including one splice-site mutation (IVS14 + 1G-->A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, I560S, D949V) and five polymorphisms (C29R, R21Q, S534N, I543V, V732I). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 + 1G-->A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G-->A mutation should be routinely carried out prior to the start of treatment with 5FU.
authors.affiliation: Academic Medical Center, University of Amsterdam, Laboratory of Genetic Metabolic Diseases, Emma Children's Hospital and Department of Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam. a.b.vankuilenburg@amc.uva.nl
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Ronney A
authors.initials: RA
authors.lastname: De Abreu
authors.forename: Albert H
authors.initials: AH
authors.lastname: van Gennip
mesh_terms: D000483:Alleles; D018389:Codon, Nonsense; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000172:deficiency*; D011110:Polymorphism, Genetic
chemical_list: D018389:Codon, Nonsense; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil