5-fluorouracil metabolic pathway (5-FU pathway)

The 5-fluorouracil (5-FU) metabolic pathway is a complex biochemical network responsible for the activation, catabolism, and therapeutic action of fluoropyrimidine drugs. 5-FU is an antimetabolite that acts as a prodrug, requiring conversion into active nucleotides such as fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP) (Longley et al., 2003, Nature Reviews Cancer). The primary mechanism of action involves the inhibition of thymidylate synthase (TYMS) by FdUMP, which depletes thymidine pools and halts DNA synthesis, alongside the incorporation of fraudulent nucleotides into RNA and DNA (StatPearls, 2023). Conversely, the enzyme dihydropyrimidine dehydrogenase (DPYD) serves as the rate-limiting step in the catabolism of 5-FU, converting it into inactive metabolites (Amstutz et al., 2018, Clinical Pharmacology & Therapeutics). Genetic variations within this pathway, particularly in the DPYD gene, are critical clinical biomarkers as they can lead to severe, potentially fatal systemic toxicities due to impaired drug clearance (CPIC, 2018). This pathway is a cornerstone of chemotherapy for various solid tumors, including colorectal, breast, and aerodigestive tract cancers (PubMed, 2023). Therapeutic modulation of the pathway often involves the use of Leucovorin to stabilize the inhibitory complex with TYMS or the use of oral prodrugs like Capecitabine (Nature Reviews Cancer, 2003).

Other names

Fluoropyrimidine metabolism5-FU metabolismPyrimidine metabolic pathway

Inhibition of thymidylate synthase and incorporation of fluorinated nucleotides into RNA and DNA