Differential effects of partial hepatectomy and carbon tetrachloride administration on induction of liver cell foci in a model for detection of initiation activity

Differential effects of partial hepatectomy (PH) and carbon tetrachloride ( CCl4) administration on induction of glutathione S-transferase placental fo rm (GST-P)-positive foci were investigated in a model for detection of init iation activity. Firstly, we surveyed cell proliferation kinetics and fluct uation in cytochrome P450 (CYP) mRNA levels by means of relative-quantitati ve real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and C YP 2E1 apoprotein amount by immunoblotting (experiment I) after PH or CCl4 administration. Next, to assess the interrelationships among cell prolifera tion, fluctuation of CYPs after PH or CCl4 administration and induction of liver cell foci, the non-hepatocarcinogen, 1,2-dimethylhydrazine (DMH) was administered to 7-week-old male F344 rats and initiated populations were se lected using the resistant hepatocyte model (experiment II). In experiment I, the values of all CYP isozyme mRNAs after PH or CCl4 administration were drastically decreased at the 12-h time point. From 72 h, mRNAs for all CYP isozymes began increasing, with complete recovery after 7 days. The CYP 2E 1 apoprotein content in the PH group fluctuated weakly, whereas in the CCl4 group it had decreased rapidly after 12 h and was still low at the 48 h po int. In experiment II, induction of GST-P-positive foci was related to cell kinetics in the PH group, with about a 6-h time lag between time for carci nogen administration giving greatest induction of GST-P-positive foci and p eaks in bromodeoxyuridine (BrdU) labeling, presumably due to the necessity for bioactivation of DMH. With CCl4 administration, induction of foci appea red dependent on the recovery of CYP 2E1. In conclusion, PH was able to ind uce cell proliferation with maintenance of CYP 2E1, therefore being advanta geous for induction of liver cell foci in models to detect initiation activ ity.