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Role of Oxyradicals in Mutagenicity and DNA Damage Induced by Crocidolite Asbestos in Mammalian Cells¹

Center for Radiological Research, College of Physicians and Surgeons [A. X., L-J. W., T. K. H.] and Division of Environmental Health Sciences, Joseph L. Mailman School of Public Health [R. M. S., T. K. H.], Columbia University, New York, New York 10032

Crocidolite, one of the most carcinogenic forms of asbestos, is mutagenic in cultured mammalian cells when assayed using a system that can detect multilocus deletions. In the present study, we examined the effect of buthionine sulfoximine (BSO) on mutation frequency and the formation of 8-hydroxydeoxyguanosine (8-OHdG) in human-hamster hybrid (A_L) cells induced by crocidolite fibers in an attempt to determine the role of oxyradicals in mediating fiber mutagenesis. BSO, a competitive inhibitor of the enzyme -glutamyl cysteine synthetase, depleted nonprotein sulfhydryls to <5% of control within 24 h at a nonmutagenic dose of 25 µM. In cells pretreated with BSO for 24 h, the mutation yield at the CD59 locus induced by a 4 µg/cm² dose of crocidolite fibers was increased by more than 3-fold (P < 0.05). Using immunoperoxidase staining with a monoclonal antibody specific for 8-OHdG, we demonstrated that crocidolite fibers induced a dose-dependent increase in oxidative DNA damage in A_L cells. Furthermore, addition of DMSO, a well-established hydroxyl radical (OH^•) scavenger, dramatically suppressed 8-OHdG induction (P < 0.005). Our results definitely demonstrate that reactive oxygen species mediate fiber-induced DNA damage mutagenesis in A_L cells in a concentration-dependent manner.

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