Callís, Montserrat Casadevall; (1995) The mode-of-action of the carcinogen chromium (VI): An investigation into the formation of DNA lesions during the reduction of chromate. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chromium(VI) is a well established human carcinogen. Chromate ions are easily taken up by the cells and, once inside, are reduced by a variety of intracellular components including cysteine, ascorbic acid and glutathione. The intracellular reduction of chromium(VI) is a necessary step in the activation to its carcinogenic form and leads to the generation of a variety of DNA lesions. This study has investigated the role of glutathione (GSH) in mediating the formation of apurinic/apyrimidinic sites (AP-sites) by chromate. The treatment of isolated bacteriophage DNA (PM2) with chromate and GSH caused the formation of AP-sites. The level of AP-sites increased with rising chromate concentrations in the presence of constant amounts of glutathione. An intermediate formed during the reduction of chromate by glutathione was responsible for the damage. AP-sites and single strand breaks (SSB) were formed in similar amounts and their generation followed an almost identical time course. Exclusion of oxygen from the incubation mixtures revealed that molecular oxygen is essential for the process leading to the activation of chromium(VI) to DNA damaging species. A possible role for molecular oxygen was further investigated by kinetic studies of the reduction of chromate by glutathione. The rate of reduction of Cr(VI) increased under anoxic conditions, suggesting a side reaction involving molecular oxygen during which a species able to damage DNA is formed. Hydroxyl radicals are not generated during the reduction process, as none of the typical DNA base adducts formed by attack of hydroxyl radicals were observed using gas chromatography/mass spectrometry in selective ion mode. The hypothesis that SSB and AP-sites are formed by attack of a reactive species at the sugar moiety of DNA was confirmed by the finding that malondialdehyde-like products were released upon treatment of calf-thymus DNA with chromate and GSH. These studies have provided evidence of a non-Fenton pathway in the formation of DNA lesions during chromate reduction, which may be of importance in the mediation of chromate carcinogenicity.

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