Reduced folate carrier and Proton-coupled folate transporter (RFC/PCFT)

The Reduced Folate Carrier (RFC/SLC19A1) and the Proton-Coupled Folate Transporter (PCFT/SLC46A1) are the two primary mediators of folate and antifolate transport across cell membranes in humans. RFC is a bidirectional facilitative transporter that operates at physiological pH and is the major route for folate uptake in systemic tissues and the primary entry point for many antifolate chemotherapeutics like methotrexate (UniProt: P41440). In contrast, PCFT is an electrogenic symporter that functions optimally in acidic environments, such as the upper small intestine and within the acidic microenvironment of solid tumors, making it essential for dietary folate absorption (PubMed: 17159991). Mutations in PCFT lead to hereditary folate malabsorption, while alterations in RFC expression are frequently associated with methotrexate resistance in various cancers (PubMed: 23613504). These transporters are critical therapeutic targets because their expression levels determine the efficacy and toxicity profiles of folate-based drugs. Understanding their distinct pH optima and tissue distributions allows for the design of next-generation antifolates that selectively target tumor cells over healthy tissues (PubMed: 24411331).

Other names

SLC19A1SLC46A1Folate transporter 1Heme carrier protein 1HCP1IFC-1Intestinal folate carrier 1

These proteins function as transmembrane transporters that facilitate the cellular uptake of folates and antifolate drugs; drugs act as substrates that are translocated into the cell to exert their pharmacological effects (PubMed: 23613504).