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 mech-anism 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 mM arsenite for 20 or more weeks) and control TRL 1215 cells were both exposed to nickel for 24 h, and cell viability was determined by metabolic integrity. The LC50 for nickel was 608 6 32 mM in CAsE cells as compared to 232 6 16 mM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 mM nickel for 4 h and cellular-free radical production was measured using ESR spectrometry. Hydroxyl radical generation was decreased in CAsE cells. Thio-barbituric acid reactive substances, indicative of lipid peroxida-tion, and 8-oxo-2*-deoxyguanosine, indicative of oxidative DNA damage, were reduced in CAsE cells. Flow cytometric analysis using Annexin/FITC revealed that nickel-induced apoptosis wa