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Altered Oxidative Stress Responses in Nickel-resistant Mammalian Cells¹

Nelson Institute of Environmental Medicine [K. S., M. G., V. V., X. H., M. C] and The Kaplan Comprehensive Cancer Center [M. C.], New York University Medical Center, New York, New York 10016

BALB 3T3 cells exposed to NiCl₂ acquired resistance to concentrations as high as 200 µM 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.

¹ This work was supported from NIH Grants ES 00260, ES 04895, ES 04715, and ES 05512, and National Cancer Institute Grant CA 16087.

² To whom all requests for reprints should be addressed, at Nelson Institute of Environmental Medicine and The Kaplan Comprehensive Cancer Center, New York University Medical Center, 550 First Avenue, New York, NY 10016.

Received 8/ 4/94. Accepted 10/19/94.

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