The reductive conversion of the carcinogen chromium (VI) and its role in the formation of DNA lesions.
The potential of Cr(VI), in combination with glutathione (GSH) or ascorbate (AsA) to induce apurinic/apyrimidinic sites (AP-sites) and single strand breaks (SSB) in isolated deoxyribonucleic acid (DNA) was investigated. The observation that both lesions were formed with equal probability and followed a similar time course suggests that they might arise from attack of a reactive species at C4' of the DNA sugar moeity. This idea is further substantiated by the finding that malondialdehyde-like products are released in chromate/GSH- and chromate/AsA-treated DNA. The generation of AP-sites and SSB was dependent on molecular oxygen and could be suppressed by the addition of catalase. Our results rule out hydroxyl radicals as the DNA damaging species. Furthermore, Cr(V), an intermediate formed during reaction with GSH or AsA, is not directly involved in the generation of DNA damage, unless activated by molecular oxygen. Our findings indicate that a superoxo- or peroxo-complex involving Cr(V) or Cr(IV) might be the species responsible for DNA damage. Evidence is presented that the DNA lesions arising from chromate/AsA have the potential to cause gene mutations.
Kortenkamp
A
A
Department of Toxicology, University of London, England.
Casadevall
M
M
Da Cruz Fresco
P
P
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000633:toxicity; D001894:Borohydrides / Q000737:chemistry; D002273:Carcinogens / Q000737:chemistry* / Q000633:toxicity; D002374:Catalase / Q000494:pharmacology; D002417:Cattle; D002857:Chromium / Q000737:chemistry* / Q000633:toxicity; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000737:chemistry / Q000633:toxicity; D066298:In Vitro Techniques; D008315:Malondialdehyde / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D001894:Borohydrides; D002273:Carcinogens; D004277:DNA, Single-Stranded; D004338:Drug Combinations; D002857:Chromium; D008315:Malondialdehyde; C025364:sodium borohydride; D002374:Catalase; D005978:Glutathione; D001205:Ascorbic Acid