S. Van Den Heiligenberg et al., The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats, LIFE SCI, 64(26), 1999, pp. 2523-2534
The hypothesis that light-induced circadian clock suppression exerts a prom
oting effect on liver carcinogenesis was investigated in rats.
Sixty-five male Wistar rats were given diethylnitrosamine (DEN, 10 mg/kg/da
y 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 phenobar
bital (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 (alpha MT6s) excretio
n, a marker of circadian clock function, had lost its circadian rhythmicity
in the LL group, with a 4-fold lower than 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 chi(2) = 0.1). no
dules were more numerous and larger both in th LL group and in th LDpheno o
ne as one compared to the LD group (p from chi(2) <0.05). All the rats died
with hepatocellular carcinomas, with a median survival of 5 months, simila
r in all 3 groups. Light-induced circadian clock suppression exerted a prom
oting effect similar to that caused by phenobarbital in this model, yet thr
ough different effects on circadian function.