Both physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safrole

Hepatic DNA adduct formation induced by the chemical carcinogen,safrole, was suppressed by both endogenous pineal melatoninrelease and by the exogenous administration of melatonin torats. DNA damage after administration of 100 mg/kg safrole (i.p.)was measured by the PI enhanced 32P-postlabeling analysis method.The RAL (relative adduct labeling) x 10⁷ of carcinogen modifiedDNA in the liver of untreated controls and in safrole treatedanimals killed during the day, at night, after pinealectomyand pinealectomy plus melatonin injection (0.15 mg/kg x 4 ora total of 0.6 mg/kg) was 0, 12.6 ± 0.75, 10.9 ±0.72, 13.6 ± 1.12 and 5.7 ± 0.53 respectively.For the same groups of animals, circulating melatonin levelsat the termination of the study were 31±3, 29 ±2, 276 ±31, 24 ± 1 and 13 950 ± 1016 pg/mlserum respectively. The higher the melatonin concentration inthe serum the lower was DNA adduct formation in the rat liver.Thus, high nocturnal levels of melatonin were protective againstsafrole-induced DNA damage. These findings indicate that thefunctional pineal gland plays an important role in oncostaticactions of carcinogens such as safrole. At physiological levels,melatonin seemed to prevent especially the formation of whatwas referred to as the Nl DNA adduct. Melatonin's ability tosuppress DNA adduct formation may relate to its inhibitory effecton a mixed function oxidase, cytochrome p-450, and on the recentlyidentified hydroxyl radical scavenging capacity of the indole.The oncostatic action of melatonin is also suggested by itsnuclear accumulation and DNA stabilization characteristics.At pharmacological levels melatonin is extremely potent in preventingDNA modification induced by the chemical carcinogen, safrole.