Comparison of different initiation protocols in the resistant hepatocyte model

Parvaneh Espandiari, Larry W. Robertson, Cidambi Srinivasan, Howard P. Glauert

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25 Scopus citations


Several models in rat liver have been developed to study multistage carcinogenesis, including the Solt-Farber resistant hepatocyte model. In this model, initiation consists of either a necrogenic dose of a hepatocarcinogen or a non-necrogenic dose in conjunction with partial hepatectomy (PH). As an alternative to PH, we investigated two different procedures: fasting for 96 h followed by refeeding, or the use of one-day-old neonates. Male Fisher 344 rats were injected p.o. with diethylnitrosamine (DEN) (0, 20, or 100 mg/kg) 24 h after refeeding or PH (controls received DEN alone with no proliferative stimulus). For the neonatal group, male and female Fisher 344 rats were treated with DEN (0 or 20 mg/kg, i.p.) at one day of age. All initiated animals were treated at the same age (11 weeks) with the following selection agents: three daily doses of 2-acetylaminofluorene (AAF) (30 mg/kg), followed by a single dose of carbon tetrachloride (2 ml/kg), followed by three additional daily treatments of AAF (30 mg/kg). Rats were euthanized 2 weeks after the last AAF injection. The PH, neonatal male, and neonatal female groups receiving DEN developed more γ-glutamyl transpeptidase (GGT)-positive foci per cubic centimeter and foci per liver as compared to untreated rats receiving the same proliferative stimulus, whereas the fasting/refeeding group and the group receiving no proliferative stimulus did not. All DEN-treated groups receiving one of the proliferative stimuli had more foci per cubic centimeter than the DEN-treated group receiving no proliferative stimulus. The volume fractions of GGT-positive foci in the PH/DEN and neonatal male/DEN groups were higher than those of both the DEN-treated group receiving no proliferative stimulus and the groups receiving the same proliferative stimulus without DEN. In neonatal females-receiving DEN, the volume fraction was not different from either neonatal females not receiving DEN or DEN-treated rats receiving no proliferative stimulus. The volume fraction in the fasting/refeeding group was increased when DEN was administered at 100 mg/kg but not at 20 mg/kg. We conclude that the use of male neonatal rats can replace the PH in the Solt-Farber protocol. Fasting/refeeding was also effective at increasing the volume fraction of GGT-positive foci, but only at the higher dose of DEN.

Original languageEnglish
Pages (from-to)373-381
Number of pages9
Issue number3
StatePublished - Jan 31 2005

Bibliographical note

Funding Information:
Authors thank Ms. Cynthia Long, Ms. Divinia Stemm, and Dr. Gabriele Ludewig, Dr. Hans Lehmler, Dr. Anandi Srinivasan, Dr. Nilufer Tampal, Dr. Job Tharappel, Dr. Karen Calfee-Mason, and Dr. Zijing Lu for assistance during this project. This project was supported by grant number ES07380 from the Superfund Basic Research Program, NIEHS; by grant no. CA01688 from NCI; and by the Kentucky Agricultural Experiment Station.


  • 2-Acetylaminofluorene
  • Diethylnitrosamine
  • Fasting
  • Neonatal
  • Partial hepatectomy

ASJC Scopus subject areas

  • Toxicology


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