Intracellular and extracellular factors influencing Cr(VI) and Cr(III) genotoxicity.
Cr(VI) is a human and animal carcinogen. Cr(VI) does not interact directly with DNA and thus its genotoxicity is attributed to its intracellular reduction to Cr(III) via reactive intermediates. The resulting types of DNA damage can be grouped into two categories: (1) oxidative DNA damage and (2) Cr(III)-DNA interactions. This study examines the molecular mechanism of Cr(VI) and Cr(III) genotoxicity in an intact cell. A system screening for DNA deletions (DEL assay) was used to compare induction of chromosomal rearrangements in the yeast Saccharomyces cerevisiae following Cr(VI) and Cr(III) exposure. Both forms of chromium induced DNA deletions albeit with different dose-response curves. N-acetylcysteine had a protective effect against Cr(VI) genotoxicity at high exposure doses but had no protective effect at lower doses or against Cr(III). An oxidative DNA damage repair mutant was hypersensitive to Cr(VI) only at high exposure and the mutant was not hypersensitive to Cr(III) exposure. These data imply that oxidative stress is involved in Cr(VI) genotoxicity at high exposure concentrations and not so in Cr(III). The Cr(III)-DNA interaction appears to be an important genotoxic lesion following Cr(VI) exposure at low-exposure concentrations. The CAN forward mutation assay revealed that within the concentration ranges used for this study, Cr(III) does not cause point mutations and Cr(VI) causes a mild but statistically significant increase in point mutation only at the highest concentration tested. This study reveals that DNA deletions occurring as a result of intrachromosomal homologous recombination are a useful endpoint for studying chromium genotoxicity.
Department of Pathology, Geffen School of Medicine and School of Public Health, UCLA, Los Angeles, California 90095, USA.
Zhanna
Z
Sobol
Robert H
RH
Schiestl
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002274:Carcinogens, Environmental / Q000378:metabolism / Q000633:toxicity*; D002460:Cell Line; D002857:Chromium / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D059765:Homologous Recombination; D059645:Mutation Rate; D010084:Oxidation-Reduction; D051381:Rats
D002274:Carcinogens, Environmental; D016166:Free Radical Scavengers; D002857:Chromium; D000111:Acetylcysteine