Melatonin attenuates estradiol-induced oxidative damage to DNA: Relevance for cancer prevention

Estrogens exert pro-oxidative effects and have been shown to damage DNA, po tentially leading to cancer. Melatonin is a well-known antioxidant, free ra dical scavenger, and oncostatic agent. Changes in the levels of 8-oxo-7,8-d ihydro-2 ' -deoxyguanosine (8-oxodGuo), an index of DNA damage, and the lev els of malondialdehyde + 4-hydroxyalkenals, an index of lipid peroxidation, were measured in kidneys, liver, and testes from hamsters treated with E-2 (75 mg/kg body wt) and were collected 3 or 5 hr later. Other animals were treated with melatonin (15 mg/kg body wt, 30 min before and 120 min after E -2 treatment) or were given both compounds. Additionally, lipid peroxidatio n was measured in liver homogenates exposed to ferrous sulfate (15 muM) in vitro. E-2 treatment caused an increase in 8-oxodGuo levels in kidneys coll ected 5 hr after E-2 administration, and in liver 3 hr after estrogen treat ment. Melatonin completely prevented E-2-induced DNA damage in both organs. Melatonin alone or when given with E-2 and examined 3 hr later decreased t he base level of 8-oxodGuo in testes. A tendency for a reduction in in vivo lipid peroxidation was observed after treatment of hamsters with either me latonin, E-2, or both compounds, with a statistically significant decrease being measured in the liver following E-2 administration. In vitro exposure to iron significantly enhanced lipid peroxidation in hepatic homogenates f rom untreated, melatonin-treated, or E-2-injected hamsters; in the hepatic homogenates of hamsters given both E-2 and melatonin, ferrous sulfate faile d to augment lipid peroxidation, Our results confirm the dual actions of es trogens relative to oxidative damage, i,e,, estrogen increases oxidative de struction of DNA while reducing lipid peroxidation, Melatonin had antioxida tive actions in reducing oxidative damage to both DNA and to membrane lipid s. Melatonin completely prevented the damaging action of E-2 on DNA and syn ergized with the steroid to reduce lipid peroxidation.