A subnecrogenic dose of diethylnitrosamine is able to initiate hepatocarcinogenesis in the rat when coupled with fasting/refeeding

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Abstract
Caloric restriction causes a generalized decrease in growth rate and has been repeatedly associated with an inhibitory effect on cancer development in several systems. In contrast, exposure to complete fasting followed by refeeding is as metabolic condition associated with increased cell turnover in different organs, including the liver. The present study examines whether such condition is able to sustain the induction of initiated hepatocytes following a subnecrogenic dose of diethylnitrosamine (DENA). Male Fisher-344 rats were fasted for 4 days and 1 day after refeeding they were given a single dose of DENA (20 or 200 mg/kg body wt, i.p.). Negative and positive control groups were fed ad libitum and injected with 20 and 200k mg/kg of DENA, respectively. One week later all animals were subjected to the resistant hepatocyte model for the selection of hepato-cyte nodules and they were killed 2 weeks thereafter. Results indicated the presence of gamma-glutamyltransfer-ase (GGT) positive foci and nodules (38 ± 7/cm2) in rats regularly fed and given 200 mg/kg of DENA, while virtually no focal lesions (2) were found in the group receiving 20 mg/kg of DENA and fed throughtout the experiment. However, a significant number of GGT positive foci/nodules (14 ± 7) also developed in rats exposed to fasting and given 20 mg/kg of DENA 24 h after refeeding. No evidence of helpatocellular necrosis was found in the latter group follwing DENA administration. No effect of fasting was observed when rats received 200 mg/kg of DENA. It is concluded that fasting/refeeding provides conditions which are able to sustain initiation in rat liver by a subnecrogenic dose of a carcinogen. These findings are in contrast with the commonly reported inhibitory effect of chronic food restriction on various stages of carcinogenesis, including initiation.

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