Methotrexate influx transporters

Methotrexate influx transporters are a specialized group of membrane proteins responsible for the cellular uptake of methotrexate and natural folates. The primary member is the Solute carrier family 19 member 1 (SLC19A1), also known as the reduced folate carrier (RFC1), which functions as an organic anion antiporter and is the dominant route for methotrexate entry at physiological pH (Matherly & Hou, 2005, PMID: 16169923). Another critical component is the Proton-coupled folate transporter (SLC46A1/PCFT), which facilitates uptake in acidic environments such as the proximal jejunum and the microenvironment of solid tumors (Zhao & Goldman, 2013, PMID: 23447567). These transporters are essential for the therapeutic efficacy of methotrexate, as the drug must reach the cytoplasm to inhibit dihydrofolate reductase and undergo polyglutamylation for intracellular retention. Alterations in the expression or function of these transporters, often through genetic mutations or epigenetic silencing, are major mechanisms of acquired resistance to methotrexate in cancer cells (Assaraf, 2007, PMID: 17448563). Furthermore, genetic variations in these transporters, such as the SLC19A1 G80A polymorphism, have been linked to variations in methotrexate efficacy and toxicity in patients treated for rheumatoid arthritis and leukemia (Inoue et al., 2003, PMID: 12851625).

Other names

Reduced folate carrier 1RFC1Solute carrier family 19 member 1SLC19A1Proton-coupled folate transporterPCFTSolute carrier family 46 member 1SLC46A1Folate transporters

Facilitated transport of methotrexate and other antifolates across the plasma membrane into the cytoplasm.