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The effects of D-galactosamine (D-gal) and carbon tetrachloride (CCl4) administration on induction of liver cell proliferation in a medium term liver bioassay for detection of initiation activity of 1,2-dimethylhydrazine (DMH) were investigated with special emphasis on kinetics of cell proliferation and cytochrome P450 (CYP) expression. In experiment I, fluctuation of cell proliferation and CYP 2E1, which is one of the enzymes involved in bioactivation DMH to ultimate form, levels of liver cells after D-gal administration (4000 mg/kg, i.g.) or CCl4 administration (1 ml/kg, i.g.) was analyzed by bromodeoxyuridine labeling and western blotting, respectively. In experiment II, induction of glutathione S-transferase placental form (GST-P)-positive foci by DMH in a model for detection of initiation activities using D-gal or CCl4 administration as a toxicity-regeneration dependent proliferative stimulus was evaluated. Although high BrdU labeling indices continued from 36 h to 72 h after D-gal and CCl4 treatment, cell proliferation after intragastric D-gal administration was very low compared with the CCl4 case. Decrease of CYP 2E1 apoprotein content in the microsomes was slight after D-gal administration, whereas decrease up to about 40% of the control level was evident from 12 h until 60 h after CCl4. When the carcinogen was injected 60 h after D-gal administration, there was appreciable increase in the area and numbers of GST-P positive foci, similar to the case with CCl4 administration. Sensitivities for detection of initiation activity with intragastric D-gal or CCl4 administration were equal, despite the kinetics of cell proliferation and CYP 2E1 being very different. With CCl4 administration, initiation depended on fluctuation of CYP 2E1, reversibly in intragastric D-gal treatment, initiation depended on cell kinetics.

journal of toxicologic pathology

The Effects of D-galactosamine- or Carbon Tetrachloride-Induced Regeneration on Induction of Rat Liver Cell Foci in a Model for Detection of Initiation Activities of Chemicals.