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 microM 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 LC(50) for nickel was 608 +/- 32 microM in CAsE cells as compared to 232 +/- 16 microM in control cells, a 2.6-fold increase. CAsE and control cells were treated with 200 microM 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.
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Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Kasprzak
K S
KS
Kadiiska
M
M
Liu
J
J
Chen
H
H
Maciag
A
A
Mason
R P
RP
Waalkes
M P
MP
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004578:Electron Spin Resonance Spectroscopy; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology*; D009152:Mutagenicity Tests / Q000379:methods; D009532:Nickel / Q000494:pharmacology / Q000633:toxicity*; D016877:Oxidants / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D005609:Free Radicals; D016877:Oxidants; D017392:Thiobarbituric Acid Reactive Substances; D009532:Nickel; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; D016650:Fluorescein-5-isothiocyanate; D001151:Arsenic