Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the committed step in degradation of the chemotherapeutic agent 5-fluorouracil (5-FU) and its prodrugs. Approximately 80% of the administered 5-FU dose is metabolized through DPD. Different variants in the DPD gene lead to a DPD deficiency, which results in limited metabolism of DPD substrates. Patients with DPD mutations carry an elevated risk of developing severe toxicities under the treatment with 5-FU. Besides the well characterized exon 14 skipping mutation, other mutations in the DPD gene are associated with 5-FU toxicity as well. Genotyping of the DPD gene can contribute to reducing the danger of severe side-effects under 5-FU treatment. Analysis of the DPD gene can be requested as a step-wise diagnostic. In step I the exon 14 skipping mutation is being examined, while in step II further mutations, more frequently mentioned in the context of 5-FU toxicity, are being detected.
Combined heterozygous or homozygous mutations in the DPD gene lead to a clinical picture of hereditary thymine uraciluria or familial pyrimidinemia.