Membrane Transport of Folates

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

“…MTX has been shown to inhibit several enzymes within the folate pathway, leading to the accumulation of antiinflammatory agents and the interruption of purine and pyrimidine synthesis (7,8). After MTX enters the cell, mainly via the reduced folate carrier or SLC19A1, folylpolyglutamate synthase catalyzes the enzymatic addition of at least 1 glutamate residue to the MTX molecule (i.e., polyglutamation), which has been shown to be a critical process for pharmacologic activity (9,10). Polyglutamation of MTX promotes retention of the drug in the cell, resulting in more opportunity for its inhibitory effects to be exerted upon its target enzymes.…”

Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy

“…Two folate transport proteins have been identified in kidney tissue: the reduced folate carrier (RFC) and the folate receptor (FR) (27,33,49,51). The RFC is found on the basolateral surface of kidney proximal tubule cells (55), while FRs are found on the apical brush-border membrane (3,12,22,24,49).…”

Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

“…The primary models used in this study included L1210 leukaemia cells that expressed either the classical RFC or MFR as the dominant route of (anti) folate cell entry. Previous notions that eYciency of RFC transport is a determining factor in the potency of hydrophilic antifolates [25,31], were re-established by revealing good correlations between RFC aYnities for antifolates and both TSI and IC 50 values for cell growth inhibition (Fig. 1).…”

“…Of these the reduced folate carrier (RFC) and membrane folate receptors (MFR) are thoroughly characterized [4,14,24,25,31,52,71]. The RFC is an integral membrane glycoprotein that generates folate uptake by a carrier-mediated process through a bi-directional anion exchange mechanism [25,31]. The RFC is characterized by a high aYnity (K m : 1-10 M) for reduced folates and methotrexate (MTX), whereas it has poor aYnity for oxidized folates such as folic acid (K m : 200-400 M).…”

“…Two mechanisms of internalization of folates by MFR have been proposed: classical endocytosis [47] and a process called potocytosis which involves the sequestration of MFRs in speciWc membrane vesicles (caveolae) in which, upon acidiWcation, the (anti) folates dissociate from the receptors and are transported into the cytosol by a putative folate carrier [2]. Although the exact role and the relative importance of the RFC in mediating antifolate antitumor activity in vivo has been fairly well established [5,29,31,50], the role of MFR is still unclear [12,67]. However, it may be anticipated that optimal MFR-mediated transport could be revealed under conditions of low extracellular folates when there is less receptor occupancy and competition with circulating reduced folates [15,61,68].…”