Abstract
The morphological and cytochemical changes occurring in liver of male Sprague-Dawley rats receiving clofibrate, diethylnitrosamine (DENA) followed by phenobarbital (PB) and PB alone were studied after administration periods varying from 3 days to 103 weeks. All treated rats showed liver enlargement and enzyme induction. While the rats receiving clofibrate showed ultrastructural and enzymic changes consistent with an enhanced lipid metabolism, all the rats treated with PB displayed morphological and cytochemical modifications indicative of stimulated drug detoxicating microsomal activity. Rats treated with clofibrate revealed foci of cellular alteration occurring sooner (week 42) than untreated controls (week 60). Approximately half of the rats which had received 68 or more weeks of continuous treatment with clofibrate developed hepatic nodules. None of the foci and nodules examined cytochemically showed γ-GT or aerobic G6PDH activities. Most of the other enzymes assayed showed an heterogeneous pattern characteristic of these liver lesions. In the rats withdrawn from clofibrate for 16 to 18 weeks, after 68 to 95 weeks of treatment no nodules were found. Although the number of Y-GT- positive foci was increased, phenobarbital alone had little effect on the incidence of foci of cellular alteration. DENA followed by PB led to the early appearance of foci of cellular alteration (from week 4), of nodules (from week 12) and hepatocellular carcinomas (from week 21). These lesions had acquired γ-GT and aerobic G6PDH, and in addition exhibited cytochemical changes reflecting a sustained activity of the microsomal drug metabolizing system and conjugative processes. DENA-PB for 17 to 30 weeks induced essentially the same lesions. Withdrawal of PB treatment for periods of 22 and 26 weeks did not diminished the incidence of liver lesions nor changed their morphological and cytochemical characteristics.