Influence of 2,3-dimercaptopropanol and other sulfur compounds on oxophenylarsine-mediated inhibition of glucose uptake in MDCK cells

Abstract

Trivalent monosubstituted organoarsenicals, e.g., oxophenylarsine (PhAsO), exert various detrimental effects on mammalian cells. In addition to their well known interference with pyruvate and ketoglutaric acid oxidation, the effect on other cellular functions such as uptake of glucose may contribute to their acute toxicity. Different effects of PhAsO on insulin-stimulated and insulin-independent uptake of hexoses in various tissues have been reported. It has been shown previously that PhAsO inhibits the stereospecific uptake of glucose in MDCK cells. In this work, the insulin dependence of glucose uptake in these cells and the effects of 2,3-dimercaptopropanol (BAL), dithiothreitol (DTT) and 2-mercaptoethanol (ME) on PhAsO-induced inhibition of glucose uptake were investigated. A 200 µmol l^–1 concentration of insulin had no measurable effect on cellular ¹⁴C accumulation from D-[6-¹⁴C]glucose, indicating an insulin-independent hexose transport system. In the presence of 2 µmol l^–1 of PhAsO, glucose uptake was lowered to less than 50% of controls within 30 min. Greater inhibition was observed with higher concentrations of PhAsO, but cell viability as assessed by formazan formation started to decrease at concentrations 5 µmol l^–1, especially after longer exposure times. When BAL was added in a ten-fold molar excess 30 min after beginning incubation with PhAsO (2 µmol l^–1), virtually complete recovery of inhibited glucose uptake occurred within 10 min after addition. ME at up to a 100-fold molar excess over arsenic had no influence on the inhibition of glucose uptake within 120 min after addition. DTT only partially reversed inhibited glucose uptake at a 100-fold molar excess over PhAsO. The findings suggest that PhAsO inhibits insulin-independent, stereospecific uptake of hexoses in MDCK cells and that this inhibition is effectively counteracted by dithiol compounds, vicinal dithiols being most effective.