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

Abstract

Chromium (Cr) compounds are known occupational and environmental carcinogens. This trace element is found in the workplace primarily in the valence forms Cr(III) and Cr(VI). Cr(III), which was thought originally to be relatively nontoxic, was recently found to be more reactive toward purified DNA than was chromium(VI). Herein, we examined the ability of Cr(III) to induce oxidative DNA damage by measuring the formation of 8-hydroxydeoxyguanosine (8-OH-dG) in purified calf thymus DNA incubated with CrCl3 plus H2O2. In this system we observed that the Cr(III)-induced formation of 8-OH-dG in isolated DNA was both dose- and time-dependent. When melatonin and related molecules, including 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (pinoline), N-acetylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, were co-incubated with CrCl3 plus H2O2, the accumulations of 8-OH-dG in DNA samples were markedly inhibited in a concentration-dependent manner. The concentrations of each indole required to reduce DNA damage by 50%, i.e. the IC50 values, were 0.48, 0.51, 0.88, 1.00 and 3.08 microM for pinoline, melatonin, N-acetylserotonin, 6-hydroxymelatonin and indole-3-propionic acid, respectively. These results suggest that one of the mechanisms by which Cr(III) may induce cancer is via Fenton-type reactions which generate the hydroxyl radical (*OH). The findings also indicate that the protective effects of melatonin and related molecules against Cr(III)-induced carcinogenesis relate to their direct *OH scavenging ability which thereby reduces the formation of the damaged DNA product, 8-OH-dG.

Effects of Exogenous Melatonin—A Review

“…Melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce electron leakage and the generation of free radicals (131). It was shown that melatonin reduced the formation of 8-hydroxy-2 -deoxyguanosine, a damaged DNA product, 60 to 70 times more effectively than some classic antioxidants (ascorbate and α-tocopherol) (125). Thus, melatonin acts as a direct scavenger of free radicals and can detoxify both reactive oxygen and reactive nitrogen species and indirectly increase the activity of antioxidative defense systems (129,131,132,156).…”

Pharmacology and Physiology of Melatonin in the Reduction of Oxidative Stress in vivo

“…Many studies have shown that melatonin is highly protective of DNA against oxidative damage. Thus, whether the initial damage to the genome is a consequence of a chemical carcinogen [6,42,75] or to ionizing radiation [44,76], the presence of melatonin greatly attenuates the DNA damage. This protective action is afforded both in vivo as well as in vitro when purified DNA is used.…”

Relative efficacies of indole antioxidants in reducing autoxidation and iron‐induced lipid peroxidation in hamster testes

“…N-acetyl-5-hydroxytryptamine (N-acetylserotonin, NAS) (Fig. 1), the immediate precursor of melatonin, protects against oxidative damage under a variety of experimental conditions [Barsacchi et al, 1998;Qi et al, 2000]. Indole-3-propionic acid (IPA) (Fig.…”

“…Indole-3-propionic acid (IPA) (Fig. 1), a deamination product of tryptophan, possesses a structure similar to that of melatonin and is a newly discovered free radical scavenger effective in preventing oxidative damage [Chyan et al, 1999;Poeggeler et al, 1999;Qi et al, 2000]. 5-hydroxy-indole-3-acetic acid (5HIAA), the main metabolite of serotonin which is excreted in urine, has been sparingly examined in relation to oxidative stress.…”