ALTERED OXIDATIVE STRESS RESPONSES IN NICKEL-RESISTANT MAMMALIAN-CELLS

BALE 3T3 cells exposed to NiCl2 acquired resistance to concentrations as high as 200 mu M and retain resistance for many generations in the absence of nickel. This resistance was not due to alterations in uptak e or to metaliothionein 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 g lutathione synthesis inhibitor buthionine sulfoximine showed that whil e glutathione turnover was more rapid in the nickel-resistant cells, i ts depletion following NiCl2 treatment of the parental BALE 3T3 cell l ine was greater than in the nickel-resistant B200 cells. The reduced l evel of binding of NFkB and AP-1 transcription factors to their DNA co nsensus sequences in B200 cells compared to wild-type cells, and their more reactive response following treatment of resistant cells with H2 O2 or buthionine sulfoximine, strengthens the hypothesis that nickel r esistance is closely allied to oxidative stress responses.