title: Arsenic induces oxidative DNA damage in mammalian cells.
abstract: Although arsenic is a well-established human carcinogen, the underlying carcinogenic mechanism(s) is not known. Using the human-hamster hybrid (A(L)) cell mutagenic assay that is sensitive in detecting mutagens that induce predominately multilocus deletions, we showed previously that arsenite is indeed a potent gene and chromosomal mutagen and that oxyradicals may be involved in the mutagenic process. In the present study, the effects of free radical scavenging enzymes on the cytotoxic and mutagenic potential of arsenic were examined using the AL cells. Concurrent treatment of cells with either superoxide dismutase or catalase reduced both the cytotoxicity and mutagenicity of arsenite by an average of 2-3 fold, respectively. Using immunoperoxidase staining with a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), we demonstrated that arsenic induced oxidative DNA damage in A(L) cells. This induction was significantly reduced in the presence of the antioxidant enzymes. Furthermore, reducing the intracellular levels of non-protein sulfhydryls (mainly glutathione) using buthionine S-R-Sulfoximine increased the total mutant yield by more than 3-fold as well as the proportion of mutants with multilocus deletions. Taken together, our data provide clear evidence that reactive oxygen species play an important causal role in the genotoxicity of arsenic in mammalian cells.
authors.affiliation: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, NY 10032, USA.
authors.forename: Maris
authors.initials: M
authors.lastname: Kessel
authors.forename: Su Xian
authors.initials: SX
authors.lastname: Liu
authors.forename: An
authors.initials: A
authors.lastname: Xu
authors.forename: Regina
authors.initials: R
authors.lastname: Santella
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D000818:Animals; D001151:Arsenic / Q000494:pharmacology* / Q000633:toxicity; D018053:Arsenites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016296:Mutagenesis / Q000187:drug effects; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D018053:Arsenites; D009153:Mutagens; D019328:Buthionine Sulfoximine; D002374:Catalase; D013482:Superoxide Dismutase; C015001:arsenite; D001151:Arsenic