BOTH PHYSIOLOGICAL AND PHARMACOLOGICAL LEVELS OF MELATONIN REDUCE DNAADDUCT FORMATION INDUCED BY THE CARCINOGEN SAFROLE

Hepatic DNA adduct formation induced by the chemical carcinogen, safro le, was suppressed by both endogenous pineal melatonin release and by the exogenous administration of melatonin to rats. DNA damage after ad ministration of 100 mg/kg safrole (i.p.) was measured by the P1 enhanc ed P-32-postlabeling analysis method. The RAL (relative adduct labelin g) 10(7) of carcinogen modified DNA in the liver of untreated controls and in safrol treated animals killed during the day, at night, after pinealectomy and pinealectomy plus melatonin injection (0.15 mg/kg x 4 or a 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 levels at the termination of the study were 31 /- 3, 29 +/- 2, 276 +/- 31, 24 +/- 1 and 13 950 +/- 1016 pg/ml serum r espectively. The higher the melatonin concentration in the serum the l ower was DNA adduct formation in the rat liver. Thus, high nocturnal l evels of melatonin were protective against safrole-induced DNA damage. These findings indicate that the functional pineal gland plays an imp ortant role in oncostatic actions of carcinogens such as safrole. At p hysiological levels, melatonin seemed to prevent especially the format ion of what was referred to as the N1 DNA adduct. Melatonin's ability to suppress DNA adduct formation may relate to its inhibitory effect o n a mixed function oxidase, cytochrome p-450, and on the recently iden tified hydroxyl radical scavenging capacity of the indole. The oncosta tic action of melatonin is also suggested by its nuclear accumulation and DNA stabilization characteristics. At pharmacological levels melat onin is extremely potent in preventing DNA modification induced by the chemical carcinogen, safrole.