Reciprocal relationship between development of glutathione S-transferase positive liver foci and proliferation of surrounding hepatocytes in rats.

The effects of 2-acetylaminofluorene (2-AAF), phenobarbital (PB) and butylated hydroxyanisole (BHA) on the competitive proliferation of glutathione S-transferase (GST-P) positive liver cell foci induced by diethylnitrosamine (DEN) and surrounding hepatocytes were studied. Rats were given a single i.p. injection of 200 mg/kg body wt of DEN and from 2 weeks later were given a diet containing 0.02% 2-AAF (group 1), 0.05% PB (group 2), 2.0% BHA (group 3), or no supplement (group 4) for 6 weeks. All rats were subjected to partial hepatectomy (PH) at the end of week 3. Animals from each group were killed 1, 2, 3 or 4 days or 1, 2, 3 or 5 weeks after PH. Sequential changes in cellular proliferations after PH were investigated by immunohistochemical staining for GST-P and autoradiography of [3H]thymidine. The development of GST-P positive foci was enhanced strongly by 2-AAF and slightly by PB and was inhibited by BHA. In the group treated with 2-AAF, proliferation of hepatocytes adjacent to foci was almost completely inhibited [labelling index (LI) = 0.4-1.5], but GST-P positive foci cells had a high LI (16.2-26.1) 1 week after PH. In the group treated with PB, proliferation of surrounding hepatocytes was slightly inhibited (LI one day after PH = 16.0) compared with that of control (LI = 24.2), but proliferation of cells in GST-P positive foci was not inhibited (LI one day after PH = 11.3; control value = 11.0). BHA retarded recovery of the LI (LI 4 days after PH = 8.1; control value, 4.0) and did not inhibit proliferation of surrounding hepatocytes. These results indicated an inverse relationship between the development of GST-P positive foci and proliferation of surrounding hepatocytes.