Altered oxidative stress responses in nickel-resistant mammalian cells.

BALB 3T3 cells exposed to NiCl2 acquired resistance to concentrations as high as 200 microM and retain resistance for many generations in the absence of nickel. This resistance was not due to alterations in uptake or to metallothionein overexpression. The nickel-resistant B200 cell line was found to also exhibit cross-resistance to hydrogen peroxide and menadione. These nickel-resistant cells had 1.8 times higher basal levels of glutathione compared to wild-type cells. Studies with the glutathione synthesis inhibitor buthionine sulfoximine showed that while glutathione turnover was more rapid in the nickel-resistant cells, its depletion following NiCl2 treatment of the parental BALB 3T3 cell line was greater than in the nickel-resistant B200 cells. The reduced level of binding of NFkB and AP-1 transcription factors to their DNA consensus sequences in B200 cells compared to wild-type cells, and their more reactive response following treatment of resistant cells with H2O2 or buthionine sulfoximine, strengthens the hypothesis that nickel resistance is closely allied to oxidative stress responses.