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 melatonin release and by the exogenous administration of melatonin to rats. DNA damage after administration of of melatonin to rats. DNA damage after administration of 100 mg/kg safrole (i.p.) was measured by the P1 enhanced 32P-postlabeling analysis method. The RAL (relative adduct labeling) x 10(7) of carcinogen modified DNA in the liver of untreated controls and in safrole 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 respectively. The higher the melatonin concentration in the serum the lower was DNA adduct formation in the rat liver. Thus, high nocturnal levels of melatonin were protective against safrole-induced DNA damage. These findings indicate that the functional pineal gland plays an important role in oncostatic actions of carcinogens such as safrole. At physiological levels, melatonin seemed to prevent especially the formation of what was referred to as the N1 DNA adduct. Melatonin's ability to suppress DNA adduct formation may relate to its inhibitory effect on a mixed function oxidase, cytochrome p-450, and on the recently identified hydroxyl radical scavenging capacity of the indole. The oncostatic action of melatonin is also suggested by its nuclear accumulation and DNA stabilization characteristics. At pharmacological levels melatonin is extremely potent in preventing DNA modification induced by the chemical carcinogen, safrole.
Tan
D
D
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284-7762.
Reiter
R J
RJ
Chen
L D
LD
Poeggeler
B
B
Manchester
L C
LC
Barlow-Walden
L R
LR
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology; D010870:Pineal Gland / Q000502:physiology / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D012451:Safrole / Q000633:toxicity*
D016588:Anticarcinogenic Agents; D004247:DNA; D008550:Melatonin; D012451:Safrole