Abstract
tert-Butylated hydroxyanisole (BHA) and 1, 2-bis(2-pyridyl)ethylene (2PY-e) are known to induce phase II drug metabolizing enzymes without inducing phase I enzymes. In this study, male F344 rats were treated with BHA, 2PY-e, or phenobarbital (PB) that is known to induce both phase I and phase II enzymes, for 7 or 28 days, and the effects of these agents on livers, in particular morphological changes, were compared. An increase in relative liver weight was observed in all treated groups. The BHA- and 2PY-e-treated groups showed significant increases in glutathione S-transferase (GST) and UDP-glucuronosyltransferase activities, while cytochrome P450 (P450) contents or 7-alkoxycoumarin O-dealkylase activities showed no change. The PB-treated group showed significant increases in both phase I and II enzyme activities. Electron microscopic examination revealed that BHA and 2PY-e did not induce apparent SER proliferation which was observed in the PB treated liver. Immunohistochemical examination revealed that BHA and 2PY-e induced GST Yp in hepatocytes of the periportal and the centrilobular area, respectively. PB did not induce GST Yp in hepatocytes. The proliferating activities of the hepatocytes treated with these agents were also evaluated using the BrdU labeling index. In the PB-and 2PY-e-treated groups, significant increases in labeling indices were found and the index was higher in the centrilobular area than in the periportal area. The labeling index of the BHA-treated group was comparable to that of the control group. The present study clarified that there were different responses in SER proliferation, inducing pattern of GST Yp and proliferating activities of hepatocytes between the PB-, 2PY-e-, and BHA-treated groups. However, mechanisms which underlie the differences found in the present study remain to be determined.
