The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats

• Published in: Life sciences (1973) Vol. 64; no. 26; pp. 2523 - 2534
• Main Authors: van den Heiligenberg, Simone, Deprés-Brummer, Petra, Barbason, Hervé, Claustrat, Bruno, Reynes, Michel, Lévi, Francis
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 1999
• Subjects: 6-sulfatoxymelatonin; Animals; Body Temperature - drug effects; Body Weight - drug effects; Carcinogens; Circadian Rhythm - drug effects; circadian rhythms; continuous light; diethylnitrosamine; Diethylnitrosamine - pharmacology; hepatocarcinogenesis; Laparotomy; Light; Liver - pathology; Liver - surgery; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - etiology; Liver Neoplasms, Experimental - pathology; Male; Melatonin - analogs & derivatives; Melatonin - urine; Motor Activity - drug effects; Phenobarbital - pharmacology; Random Allocation; Rats; Rats, Wistar; Survival Rate; 6-sulfatoxymelatonin; diethylnitrosamine; hepatocarcinogenesis; circadian rhythms; continuous light
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(99)00210-6

The hypothesis that light-induced circadian clock suppression exerts a promoting effect on liver carcinogenesis was investigated in rats. Sixty-five male Wistar rats were given diethylnitrosamine (DEN, 10 mg/kg/day p.o.) for 6 weeks and were randomized into 3 groups. Rats from group 1 (N = 20) received DEN only. Rats from group 2 (N = 22) also received phenobarbital (pheno, 30 mg/rat/day p.o.) for 4 weeks as a promoting agent and rats from group 3 (N = 23) were exposed to continuous light. Three months after starting DEN treatment, urinary 6-sulfatoxymelatonin (αMT6s) excretion, a marker of circadian clock function, had lost its circadian rhythmicity in the LL group, with a 4-fold lower 24h mean than that found in the LDpheno and LD groups (8.0 ± 3.2 ng ml , 33.6 ± 3.1 ng ml and 34.3 ± 2.4 ng ml respectively; p from ANOVA < 0.001). Laparotomy was then performed. The proportion of rats with macroscopic nodules on liver surface was 72% (LD group), 89% (LDpheno group) and 95% (LL group) (p from χ 2 = 0.1). Nodules were more numerous and larger both in the LL group and in the LDpheno one as compared to the LD group (p from χ 2 < 0.05). All the rats died with hepatocellular carcinomas, with a median survival of 5 months, similar in all 3 groups. Light-induced circadian clock suppression exerted a promoting effect similar to that caused by phenobarbital in this model, yet through different effects on circadian system function.