Reduced folate pool (RFP)

The reduced folate pool refers to the collective group of intracellular tetrahydrofolate (THF) derivatives that serve as essential carriers of one-carbon units (StatPearls, 2023). These derivatives, including 5,10-methylene-THF and 10-formyl-THF, are vital for the de novo synthesis of purine nucleotides and thymidylate, which are the building blocks of DNA (NIH, 2022). In the context of cancer therapy, the reduced folate pool is a critical metabolic target; antifolate drugs like methotrexate deplete this pool by inhibiting dihydrofolate reductase (DHFR), thereby arresting DNA replication and cell division (PubChem, 2024). Additionally, the efficacy of certain chemotherapy agents, such as 5-fluorouracil, is dependent on the availability of specific reduced folates to stabilize the inhibition of thymidylate synthase (NCBI, 2023). Beyond oncology, maintaining an adequate reduced folate pool is essential for preventing neural tube defects during embryonic development and for supporting normal erythropoiesis (Mayo Clinic, 2023). Therapeutic modulation often involves the use of leucovorin to bypass metabolic blocks or to enhance the cytotoxic effects of other antimetabolites (StatPearls, 2023).

Other names

Intracellular folate poolTetrahydrofolate poolReduced folatesOne-carbon metabolism poolActive folate pool

Drugs modulate the reduced folate pool through two primary strategies: depletion and supplementation. Antifolates like methotrexate inhibit dihydrofolate reductase (DHFR), preventing the conversion of dihydrofolate to tetrahydrofolate and thus exhausting the pool of active one-carbon donors (StatPearls, 2023). Conversely, drugs like leucovorin (folinic acid) provide an exogenous source of reduced folates that bypasses the need for DHFR, allowing for 'rescue' of normal cells or potentiation of thymidylate synthase inhibition by 5-fluorouracil (NCBI, 2023).