Avtor/Urednik		Filipič, Metka; Hei, Tom K
Naslov		Mutagenicity of cadmium in mammalian cells: implication of oxidative DNA damage
Tip		članek
Vir		Mutat Res
Vol. in št.		Letnik 546
Leto izdaje		2004
Obseg		str. 81-91
Jezik		eng
Abstrakt		Cadmium and cadmium compounds are well established human carcinogens and are ubiquitously present in the environment. The carcinogenic mechanism(s) of cadmium remains largely unknown since direct mutagenic effect is weak in bacterial and in standard mammalian cell mutation assays. In this study, we show that when evaluated using the human-hamster hybrid A1, cell mutation assay in which both intragenic and multilocus deletions can readily be detected, CdClz is a strong mutagen that induces predominantly large deletion mutations. Concun-ent treatment of A1, cells with the oxyradical scavcnger dimethyl sulfoxide significantly reduced the number of cadmium-induced mutations. In contrast, pre-treatment of cclls with buthionine sulfoximine that depletes intracellular glutathione, increased cytotoxicity and mutagenicity of cadmium. These results demonstrate that reactive oxygen species mediate cadmium induced mutations in A` cells. With laser scanning confocal microscopy and the fluorescent probe 5-(and-6)-chloromethyl-2',7'-dichlorodihydroftuorescein diacetate, we demonstrated that cadmium induced a dose and time dependent formation of intracellular oxyradicals. Using immunoperoxidase staining coupled with a monoclonal antibody-specific for 8-OHdG adducts in DNA, we demonstrated that cadmium induced a dose dependent incrcase of 8-OHdG adducts, which accumulated with prolonged exposure. Furthennore, we showed that at low concentration, cadmium, attenuated removal of hydrogen peroxide induced 8-OHdG adducts. Thus, the carcinogenicity of cadmium can, in part, be explained by its mutagenic activity, which is mediated by reactive oxygen specics induced DNA damage and by its interference with the repair of oxidative DNA damage.
Deskriptorji		HYBRID CELLS CADMIUM MUTAGENICITY TESTS REACTIVE OXYGEN SPECIES DNA DAMAGE DNA REPAIR CADMIUM CHLORIDE MICROSCOPY, CONFOCAL POLYMERASE CHAIN REACTION DIMETHYL SULFOXIDE BUTHIONINE SULFOXIMINE CELL SURVIVAL