5-Fluorouracil catabolic pathway (5-FU catabolic pathway)

The 5-Fluorouracil (5-FU) catabolic pathway is the primary metabolic route for the clearance of fluoropyrimidine chemotherapeutic agents, which are widely used in the treatment of solid tumors [Amstutz et al., 2018; Longley et al., 2003]. Over 80% of administered 5-FU is rapidly degraded in the liver through a sequential three-step enzymatic process, with dihydropyrimidine dehydrogenase (DPD) serving as the initial and rate-limiting enzyme [Diasio & Harris, 1989]. DPD converts 5-FU into 5,6-dihydrofluorouracil, which is subsequently processed by dihydropyrimidinase and beta-ureidopropionase into inactive metabolites like alpha-fluoro-beta-alanine [Wigle et al., 2019]. Because this pathway determines the systemic exposure and half-life of 5-FU, genetic variations or deficiencies in the enzymes—particularly DPD—can lead to profound drug accumulation and severe, potentially fatal, treatment-related toxicities such as myelosuppression and gastrointestinal distress [Amstutz et al., 2018]. Pharmacological inhibition of this pathway (e.g., using gimeracil or eniluracil) is sometimes employed to enhance the oral bioavailability and therapeutic index of fluoropyrimidines by preventing their rapid degradation [Longley et al., 2003].

Other names

Fluorouracil degradation pathwayUracil catabolic pathwayDPD pathwayFluoropyrimidine catabolismFluorouracil catabolism

The pathway facilitates the multi-step enzymatic degradation of 5-fluorouracil into inactive metabolites, starting with the rate-limiting reduction by dihydropyrimidine dehydrogenase (DPD) to 5,6-dihydrofluorouracil, followed by ring opening by dihydropyrimidinase (DHP) and final conversion to fluoro-beta-alanine by beta-ureidopropionase (BUP) [Diasio & Harris, 1989; Wigle et al., 2019].