Membrane transport of folates.

The chapter reviews the current understanding of the transport mechanisms for folates in mammalian cells--their molecular identities and organization, tissue expression, regulation, structures, and their kinetic and thermodynamic properties. This encompasses a variety of diverse processes. Best characterized is the reduced folate carrier, a member of the SLC19 family of facilitative carriers. But other facilitative organic anion carriers (SLC21), largely expressed in epithelial tissues, transport folates as well. In addition to these bi-directional carrier systems are the membrane-localized folate receptors alpha and beta, that mediate folate uptake unidirectionally into cells via an endocytotic process. There are also several transporters, typified by the family of multidrug resistance-associated proteins, that unidirectionally export folates from cells. There are transport activities for folates, that function optimally at low pH, related in part to the reduced folate carrier, with at least one activity that is independent of this carrier. The reduced folate carrier-associated low-pH route mediates intestinal folate transport. This review considers how these different transport processes contribute to the generation of transmembrane folate gradients and to vectorial flows of folates across epithelia. The role of folate transporters in mouse development, as assessed by homologous deletion of folate receptors and the reduced folate carrier, is described. Much of the focus is on antifolate cancer chemotherapeutic agents that are often model surrogates for natural folates in transport studies. In particular, antifolate transport mediated by the reduced folate carrier is a major determinant of the activity of, and resistance to, these agents. Finally, many of the key in vitro findings on the properties of antifolate transporters are now beginning to be extended to patient specimens, thus setting the stage for understanding response to these drugs in the clinical setting at the molecular level.