MECHANISM OF TAMOXIFENS RETINAL TOXICITY, STUDIED IN PIG PIGMENT EPITHELIAL-CELL CULTURES

The anticancer drug tamoxifen is widely used in breast cancer therapy. Tamoxifen has been reported to cause ocular toxicity and impairment o f vision in epidemiological studies. To study the possible role of an excitotoxic mechanism in the ocular toxicity of tamoxifen, we investig ated the effect of tamoxifen on retinal pigment epithelium (RPE) gluta mate uptake in vitro. RPE, a layer of cells between photoreceptors and choroidal capillaries, contributes to the regulation of the concentra tion of the major excitatory amino acid, glutamate, in the subretinal space. Dysfunction in RPE glutamate uptake can lead to accumulation of extracellular glutamate and can cause various excitotoxic effects in the retina. The study was conducted by using cultured pig RPE cells. S ix different tamoxifen citrate concentrations, ranging from 1 mu M to 100 mu M, and [H-3]-L-glutamate were added to the culture medium. To s pecify the glutamate uptake, 1mM dinitrophenol was added and a Na+-fre e culture was used. Due to the anti-oestrogenic character of tamoxifen , the possible effect of beta-oestradiol on the glutamate uptake of RP E was also examined. The results show that glutamate uptake by RPE cel ls was reduced in the presence of tamoxifen, and that the reduction wa s dose-dependent. These results suggest that tamoxifen exposure could lead to the extracellular accumulation of glutamate. Disturbances in g lutamate uptake can cause eye toxicity via an excitotoxic mechanism. T he glutamate uptake of RPE cells was reduced under Na+-free conditions and was also reduced in the presence of dinitrophenol.