DNA damage by oxo- and peroxo-chromium(v) complexes: insight into the mutation and carcinogenesis mechanisms

Abstract

The carcinogenic and mutagenic properties of chromium(vi) compounds are attributed to hypervalent chromium species, especially metastable oxo- and peroxo-chromium(v)/(iv) complexes. To understand the nature of DNA damage induced by various hypervalent chromium complexes, reactions of sodium bis(2-ethyl-2-hydroxybutanato)oxochromate(v) (I) with single- and double-stranded DNA were investigated in the presence of hydrogen peroxide and a radical scavenger. In these reactions, three DNA damaging agents, oxo- and peroxo-chromium(v) complexes and hydroxyl radicals, were generated. Both double and single-stranded DNA cleavages were largely observed after piperidine treatment, indicating base-labile scissions. Although these cleavages appeared to be random in most cases, a modest selectivity towards the G base was observed for the double stranded oligonucleotides. A variety of sugar and base oxidation products were detected after enzymatic digestion of the reaction mixtures with exo- and endo-nucleases. These products include furfural, 5-methylene furanone, 8-oxo-7,8-dihydro-2′-guanosine (8-oxodGuo), thymine propenal, deoxyribonucleoside derivative of 5-guanidinohydantoin (dGh), cytosine glycol and 5-hydroxy cytosine. The first three mentioned products were observed for reactions of compound I with DNA in the absence of peroxide. Since compound I generated a persistent peroxo-chromium(v) complex in situ and oxidation of DNA by the oxo-chromium(v) was relatively slow, it appears that the peroxo-species was largely responsible for the formation of dGh through a four-electron oxidation of the guanine residue following the mechanism proposed by Meunier and coworkers. Likewise, the formation of propenals follows a similar pathway observed for bleomycine-mediated DNA oxidation that follows Hecht's mechanism. On the other hand, 5,6-dihydroxy-5,6-dihydro-2′-deoxycytidine (dCydGl) and 5-hydroxy-2′-deoxycytidine (5-OHdCyd) were most likely formed from the reactions of DNA with the hydroxyl radical. We hypothesize that base oxidations and the formation of abasic sites are most likely responsible for transverse DNA mutation. Reactions of DNAs with a chromium(v)-peroxo complex, generated in situ, yielded both sugar and base oxidation products including guanidinohydantoin.