Mechanisms of arsenic-induced cross-tolerance to nickel cytotoxicity, genotoxicity, and apoptosis in rat liver epithelial cells

The purpose of the present study was to investigate the mechanism of cross- tolerance to nickel in arsenic-transformed cells. Chronic arsenite-exposed (CAsE) cells (TRL 1215 cells, which had been continuously exposed to 0.5 mu M arsenite for 20 or more weeks) and control TRL 1215 cells were both expos ed to nickel for 24 h, and cell viability was determined by metabolic integ rity. The LC50 for nickel was 608 +/- 32 muM in CAsE cells as compared to 2 32 +/- 16 muM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 muM nickel for 4 h and cellular-free radical product ion was measured using ESR spectrometry. Hydroxyl radical generation was de creased in CAsE cells. Thiobarbituric acid reactive substances, indicative of lipid peroxidation, and 8-oxo-2'-deoxyguanosine, indicative of oxidative DNA damage, were reduced in CAsE cells. Flow cytometric analysis using Ann exin/FITC revealed that nickel-induced apoptosis was reduced in CAsE cells. CAsE cells showed generalized resistance to oxidant-induced toxicity as ev idenced by a marked reduction in sensitivity to hydrogen peroxide. Interest ingly, intracellular reduced glutathione (GSH) levels were significantly in creased in CAsE cells, and when GSH was depleted, CAsE cells lost their nic kel resistance. The mechanism of arsenic-induced cross-tolerance to cytotox icity, genotoxicity, and apoptosis induced by nickel appears related to a g eneralized resistance to oxidant-induced injury, probably based, at least i n part, in increased cellular GSH levels.