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Toxicological Sciences 63, 189-195 (2001)
Copyright © 2001 by the Society of Toxicology

MOLECULAR AND GENETIC TOXICOLOGY

Mechanisms of Arsenic-Induced Cross-Tolerance to Nickel Cytotoxicity, Genotoxicity, and Apoptosis in Rat Liver Epithelial Cells

Wei Qu*, Kazimierz S. Kasprzak{dagger}, Maria Kadiiska{ddagger}, Jie Liu*, Hua Chen*, Anna Maciag{dagger}, Ronald P. Mason{ddagger} and Michael P. Waalkes*,1

* Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences; {dagger} Metals Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Maryland; {ddagger} Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

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 µM 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 ± 32 µM in CAsE cells as compared to 232 ± 16 µM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 µM nickel for 4 h and cellular-free radical production was measured using ESR spectrometry. Hydroxyl radical generation was decreased 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 Annexin/FITC revealed that nickel-induced apoptosis was reduced in CAsE cells. CAsE cells showed generalized resistance to oxidant-induced toxicity as evidenced by a marked reduction in sensitivity to hydrogen peroxide. Interestingly, intracellular reduced glutathione (GSH) levels were significantly increased in CAsE cells, and when GSH was depleted, CAsE cells lost their nickel resistance. The mechanism of arsenic-induced cross-tolerance to cytotoxicity, genotoxicity, and apoptosis induced by nickel appears related to a generalized resistance to oxidant-induced injury, probably based, at least in part, in increased cellular GSH levels.

Key Words: nickel; arsenic; lipid peroxidation; free radical; DNA damage; apoptosis; GSH.


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