Glutamate uptake is inhibited by tamoxifen and toremifene in cultured retinal pigment epithelial cells.

The systemic drugs chloroquine and tamoxifen have caused retinal defects in human eye. The aim of our study was to investigate the effects of the amphiphilic drug tamoxifen, of its homologue toremifene, and of chloroquine on the glutamate uptake in retinal pigment epithelial (RPE) cells. Cultured human RPE cell line D407 and pig RPE cells were used in the study. Glutamate uptake was characterised and the glutamate transporters of pig RPE cells and the human RPE cell line D407 were compared to each other. The uptake of glutamate was studied using L-[3H]glutamate as a tracer. The radioactivity in the solubilised RPE was measured with a liquid scintillation counter. In the uptake experiments, the cells were exposed to the test drugs, to the selected glutamate receptor antagonists, and to the glutamate transporter inhibitors. Both RPE cell types exhibited a high-affinity transport system for glutamate. The glutamate transporter in RPE exhibited features characteristic of the uptake systems of neurotransmitters. The transport was Na+-dependent, and L- and D-aspartate were transported into the cell by the same transporter. Chloroquine had no effect on glutamate uptake, but tamoxifen and toremifene decreased the glutamate uptake of RPE cells dose-dependently both in pig RPE cells and in human RPE cell line. The IC50 values of tamoxifen and toremifene were lower for pig RPE cells, compared to the human RPE cell line D407. The glutamate uptake was a sensitive target for the effects of tamoxifen and toremifene, and disturbances in this function could be considered as one of the possible mechanisms of retinal defects.