Dihydropyrimidine dehydrogenase [NADP(+)] (DPD) (DPD)

Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the rate-limiting enzyme in the catabolism of pyrimidine bases and the fluoropyrimidine chemotherapy drug 5-fluorouracil (5-FU) (UniProt P29760). It converts 5-FU into the inactive metabolite 5,6-dihydrofluorouracil, a process that accounts for the clearance of over 80% of the drug (PubMed: 10486648). In the context of Tegafur/UFT therapy, DPD activity is a critical determinant of the therapeutic index, as Tegafur is a prodrug of 5-FU and UFT contains uracil to inhibit DPD (PubMed: 11433132). Research has demonstrated that cyclophosphamide can modulate DPD activity, potentially suppressing the enzyme to enhance the antitumor efficacy of 5-FU-based regimens (PubMed: 11433132). Genetic deficiencies in DPD lead to severe, potentially fatal toxicities such as myelosuppression and neurotoxicity when patients are treated with standard doses of fluoropyrimidines (StatPearls: Dihydropyrimidine Dehydrogenase Deficiency). Consequently, DPD is both a metabolic target for drug-drug interactions and a vital biomarker for personalized oncology.

Other names

DPYDDihydrouracil dehydrogenaseDihydrothymine dehydrogenaseNADP-dependent dihydropyrimidine dehydrogenase

Dihydropyrimidine dehydrogenase (DPD) catalyzes the rate-limiting reduction of 5-fluorouracil (5-FU) to 5,6-dihydrofluorouracil, thereby regulating the systemic concentration of the active drug. In combination therapies like Tegafur/UFT, DPD is intentionally inhibited by components like uracil to increase 5-FU half-life. Cyclophosphamide further modulates this pathway by decreasing DPD activity, which enhances the therapeutic effect of 5-FU prodrugs but also necessitates careful monitoring for increased toxicity.