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

Carcinogenesis. 1996 Feb;17(2):289-92. doi: 10.1093/carcin/17.2.289.


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 a 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 200 mg/kg of DENA, respectively. One week later all animals were subjected to the resistant hepatocyte model for the selection of hepatocyte nodules and they were killed 2 weeks thereafter. Results indicated the presence of gamma-glutamyltransferase (GGT) positive foci and nodules (38 +/- 7/cm2) in rats regularly fed and given 200 mg/kg of DENA, while virtually no focal lesions (< 1/cm2) were found in the group receiving 20 mg/kg of DENA and fed throughout 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 hepatocellular necrosis was found in the latter group following 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / administration & dosage
  • Carcinogens / toxicity*
  • Diethylnitrosamine / administration & dosage
  • Diethylnitrosamine / toxicity*
  • Eating*
  • Enzyme Induction / drug effects
  • Fasting*
  • Glutathione Transferase / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver Neoplasms, Experimental / chemically induced*
  • Liver Neoplasms, Experimental / enzymology
  • Male
  • Rats
  • Rats, Inbred F344
  • gamma-Glutamyltransferase / metabolism


  • Carcinogens
  • Diethylnitrosamine
  • gamma-Glutamyltransferase
  • Glutathione Transferase