Increased levels of oxidatively damaged DNA induced by chromium(III) and H2O2: protection by melatonin and related molecules

Chromium (Cr) compounds are known occupational and environmental carcinogen s. This trace element is found in the workplace primarily in the valence fo rms Cr(III) and Cr(VI). Cr(III), which was thought originally to be relativ ely nontoxic, was recently found to be more reactive toward purified DNA th an was chromium(VI). Herein, we examined the ability of Cr(III) to induce o xidative DNA damage by measuring the formation of 8-hydroxydeoxyguanosine ( 8-OH-dG) in purified calf thymus DNA incubated with CrCl3 plus H2O2. In thi s system we observed that the Cr(III)-induced formation of 8-OH-dG in isola ted DNA was both dose- and time-dependent. When melatonin and related molec ules, including 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (pinoline), N-a cetylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, were co-inc ubated with CrCl3 plus H2O2, the accumulations of 8-OH-dG in DNA samples we re markedly inhibited in a concentration-dependent manner. The concentratio ns of each indole required to reduce DNA damage by 50%, i.e. the IC50 value s, were 0.48, 0.51, 0.88, 1.00 and 3.08 mu M for pinoline, melatonin, N-ace tylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, respectively. These results suggest that one of the mechanisms by which Cr(III) may indu ce cancer is via Fenton-type reactions which generate the hydroxyl radical ((OH)-O-.). The findings also indicate that the protective effects of melat onin and related molecules against Cr(III)-induced carcinogenesis relate to their direct (OH)-O-. scavenging ability which thereby reduces the formati on of the damaged DNA product, 8-OH-dG.