Interaction of human multidrug and toxin extrusion 1 (MATE1) transporter with antineoplastic agents.

Abstract

Background: The transport of endogenous and exogenous organic cations across the plasma membrane of cells is mediated by multispecific organic cation transporters (OCTs), and the multidrug and toxin extrusion (MATE) transporters. MATE belongs to the SLC47 transporter family consisting of only two members, MATE1 and MATE2-K. MATE2-K is exclusively expressed in the kidney at the apical membrane of proximal tubular epithelial cells. MATE1 is highly expressed in the kidney, liver, skeletal muscle and also in adrenal glands, testes and heart. MATE1 exchanges organic cations against protons both in influx as well as in efflux modes.

Methods: Here, we examined the interaction of 25 antineoplastic agents with human MATE1. We generated stably transfected MATE1-HEK293 cells and determined the inhibition of MATE1-mediated [(3)H]1-methyl-4-phenylpyridinium (MPP) uptake by the antineoplastic agents.

Results: We found a significant inhibition of MATE1-mediated MPP uptake by several antineoplastic agents and pH dependent IC(50)values for mitoxantrone (7.8 μM at pH 7.4 and 0.6 μM at pH 8.5) as well as for irinotecan (4.4 μM at pH 7.4 and 1.1 μM at pH 8.5), respectively.

Conclusions: We suggest that hMATE1 could play a role in chemosensitivity of tumor cells. In addition, hepatic and renal MATE1 could potentially be involved in drug-drug-interactions as well as in drug metabolism and excretion during chemotherapy.