REVERSAL OF OXOPHENYLARSINE-INDUCED INHIBITION OF GLUCOSE-UPTAKE IN MDCK CELLS

It has been shown that oxophenylarsine (PhAsO) inhibits glucose uptake in MDCK cells. In addition to the known impairment of cellular energy metabolism, this inhibition may contribute to the acute toxicity of t rivalent organic arsenicals. We have investigated the effect of BAL, D MPS, DMSA, and other sulfur compounds on cellular incorporation of [U- C-14]PhAsO and their efficacy to revert PhAsO-induced inhibition of gl ucose uptake. In the presence of [U-C-14]PhAsO (2 mu M), the radiolabe l was steadily accumulated by the cells over 150 min without any signs of severe cell damage (e.g., altered morphology, increased LDH releas e). A notable decrease of cellular ATP was only observed at 150 min, w hereas within 30 min uptake of D-[6-C-14]glucose was reduced to 40% of controls. When BAL, DMPS, or DMSA was added after 30 min, the inhibit ion of glucose uptake was reversed, accompanied by a decrease in cell- associated radiolabel from [U-C-14]PhAsO. Water-soluble DMPS and DMSA required longer times than BAL for comparable effects. 2,3-Bis(acetylt hio)propanesulfonamide, a thioester derivative, and dithiothreitol, a 1,4-dithiol, were effective only with the highest concentration tested (200 mu M). 2-Mercaptoethanol neither reversed inhibition of glucose uptake nor influenced [U-C-14]PhAsO incorporation. Our results show th at inhibition of glucose uptake is a very early event in PhAsO cytotox icity which occurs before any decrease of cellular energy metabolism a nd/or full cellular loading with arsenic comes into effect. The more r apid onset of action of lipophilic BAL compared to either DMPS or DMSA indicates better access to the sites of PhAsO action. (C) 1995 Societ y of Toxicology.