Dihydropyrimidine dehydrogenase activity and its genetic aberrations

摘要

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases, uracil and thymine, and is also known to be the key enzyme catalyzing the metabolic degradation of the anti-cancer drug 5-fluorouracil (5-FU). 5-FU has been commonly and widely used as a chemotherapeutic agent for the treatment of cancer of the gastrointestinal tract, breast, and head and neck. More than 85% of the administered 5-FU is catabolized by DPD.The clinical importance of DPD has been demonstrated with the identification of severe or lethal toxicity in patients administered 5-FU who are deficient in or have low levels of DPD activity in their peripheral blood mononuclear cells (PBMC). The importance of the role of DPD in 5-FU chemotherapy also has been shown by studies with competitive and irreversible DPD inhibitors. Population studies of DPD activity in PBMC were reported in healthy volunteers and cancer patients to evaluate the incidence of complete or partialDPD deficiency. In these studies, considerable variation was observed, and the frequency of low or deficient DPD activity (<30% and <10% of the mean activity of the normal population, respectively), was estimated to be 3-5% and 0.1%,respectively. We also found one healthy volunteer (0.7% of the population) with very low PBMC-DPD activity due to heterozygosity for a mutant allele of the DPYD gene in a population of 150 healthy Japanese volunteers. To date, at least 34 DPYD variants have been reported. However, genotyping of cancer patients with reduced or normal DPD activity showed that only 17% of those patients had a molecular basis for their deficient phenotype, which emphasized the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo,suggesting that it is difficult to identify DPD deficiency by genotyping. Therefore, it is important to develop methods for identifying DPD deficiency in cancer patients by phenotyping before 5-FU treatment.