Non-genotoxic hepatocarcinogenesis may involve suppression of the hepatocyte apoptosis that would normally remove damaged or initiated cells. These protected hepatocytes could then remain as preferential targets for promotion by this class of compounds. Here, we demonstrate clearly that the non-genotoxic liver carcinogens and hepatomitogens cyproterone acetate (CPA) and nafenopin, a peroxisome proliferator, both suppressed the basal level of rat liver apoptosis in vivo to 17 or 77% of controls, respectively. Concomitant with this suppression of apoptosis, BrdU labelling indices and mitotic figures rose confirming a perturbation of both sides of the growth equation between cell death and replication. Withdrawal of CPA or nafenopin resulted in a 100 to 200fold elevation in apoptosis. Tlus was idubited by the readnunstration of either compound. generated upon withdrawal of CPA or nafenopin. Rats were administered BrdU during the hyperplastic phase of compound administration (0-10 days). Livers were examined 5 days after compound withdrawal. With both CPA and nafenopin, apoptotic b d e s and S-phase were predominantly in the periportal region. However, despite this zonal co-localisation , very few (

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