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 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.
Qi
W
W
Department of Cellular and Structural Biology, The University of Texas Health Sciences Center, San Antonio 78284-7762, USA.
Reiter
R J
RJ
Tan
D X
DX
Manchester
L C
LC
Siu
A W
AW
Garcia
J J
JJ
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity; D002417:Cattle; D002857:Chromium / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology
D002243:Carbolines; D002273:Carcinogens; D016166:Free Radical Scavengers; D007211:Indoles; D002857:Chromium; C002272:6-methoxytryptoline; D012701:Serotonin; C015292:indolepropionic acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; D008550:Melatonin; C006389:N-acetylserotonin; C012365:6-hydroxymelatonin