Title: Pharmacogenetic Syndrome of Dihydropyrimidine Dehydrogenase Deficiency
Volume: 5
Issue: 1
Author(s): Hui-Hua Hsiao and Sheng-Fung Lin
Affiliation:
Keywords:
DPD protein, dihydropyrimidine dehydrogenase gene (DPYD), Missense Mutation, polymorphisms, 5-fluorouracil
Abstract: Dihydropyrimidine dehydrogenase (DPD), which is the initial and rate-limiting enzyme of the degradation of pyrimidine base, plays an important role in the pharmacogenetic syndrome of 5-fluorouracil (5-FU). Deficiency of DPD activity leads to severe toxicities, even death, in patients after administering 5-FU. Several studies demonstrate that the molecular defects of the dihydropyrimidine dehydrogenase gene (DPYD) lead to the deficiency of DPD activity and cause this pharmacogenetic syndrome. However, polymorphic DPD activity and complex nature of the DPYD sometimes result in conflicting findings. To date, more than 40 variant alleles, including 2 splice-site mutations, 2 nonsense mutations, 5 deletion mutations, 32 missense mutations and 2 slice mutations have been reported in the coding area of the DPYD gene. The IVS14+1G > A, which leads to the skipping of the exon 14 resulting in profound DPD deficiency and severe toxicities, is the most common mutation with 5-FU toxicity in Europeans. In addition, the epigenetic factors also participate in the clinical presentations of the syndrome. Due to the fact that the regulation mechanism of DPD itself has not been clearly clarified yet, high-throughput techniques to screen the whole DPYD and the measurement of the DPD activity are warranted to draw a clear relationship between the phenotype and genotype for this pharmacogenetic syndrome. Screening for genetic DPYD defects, at least IVS14+1G > A, and/or the DPD activity before 5-FU therapy to protect patients from hazardous outcome is also suggested, especially in specific populations.
