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Chemopreventive Effects of Melatonin on Diethylnitrosamine and Phenobarbital-Induced Hepatocarcinogenesis in Male F344 Rats

Rahman, K.M. Wahidur, Sugie, Shigeyuki, Watanabe, Tomoyuki, Tanaka, Takuji, Mori, Hideki
Nutrition and cancer 2003 v.47 no.2 pp. 148-155
adenoma, antineoplastic agents, body weight, chemoprevention, diet, diethylnitrosamine, drinking water, glutathione transferase, hepatoma, liver, males, melatonin, ornithine decarboxylase, phenobarbital, rats
The antitumor effects of melatonin on diethylnitrosamine (DEN)-initiated and/or phenobarbital (PB)-promoted hepatocarcinogenesis were investigated in male F344 rats. Five-week-old male F344 rats were divided into eight groups. Rats in groups 1-5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 wk, whereas those in groups 6-8 received vehicle treatment. Groups 1-3 and 7 were given 500 ppm PB in drinking water for 20 wk after DEN or vehicle treatment. Group 2 was given 400 ppm melatonin-containing diet during the initiation phase. Groups 3 and 5 were fed melatonin-containing diet for 20 wk, starting 1 wk after the last dosing of DEN. Group 6 was given melatonin-containing diet alone throughout the experiment (24 wk). Group 8 was treated with vehicle alone. Liver neoplasms were recognized only in DEN-treated groups. The incidences and multiplicities of hepatocellular adenoma and hepatocellular carcinoma (HCC) in group 3 were significantly smaller when compared with group 1 (P < 0.001 or P < 0.002). The average and unit areas of glutathione S-transferase placental form (GST-P)-positive foci of groups 2 and 3 were significantly smaller than those of group 1 (P < 0.001 or P < 0.01). The density and average area of these preneoplastic lesions of group 5 were also smaller than those of group 4 (P < 0.001 or P < 0.005). In addition, the ornithine decarboxylase activity in nonneoplastic liver tissue was reduced by melatonin treatment in both the initiation and postinitiation phases. These results suggest that melatonin has an antitumor-promoting ability in DEN-initiated and PB-promoted hepatocarcinogenesis in rats.