Effects of Non-Genotoxic Hepatocarcinogens Phenobarbital and Nafenopin on Phenotype and Growth of Different Populations of Altered Foci in Rat Liver ∗

Abstract

Non-genotoxic hepatocarcinogens share the ability to induce liver growth in rodents. Phenobarbital (PB), as one prototype compound, promotes the development of liver tumors; altered cell foci of the clear-eosinophilic phenotype, also identified by gamma-glutamyltransferase expression, appear to be precursor lesions. These foci seem to over-respond to the growth-inducing effect of PB. In contrast, the question as to whether peroxisome inducers are also tumor promoters is still unsettled. We will present evidence which strongly suggests that the peroxisome inducer, nafenopin (Naf), promotes tumor development in rat livers by stimulating selective growth of a hitherto undescribed subtype of altered foci. This subtype is characterized by weak diffuse cytoplasmic basophilia of its hepatocytes. Initiation in rats by aflatoxin B₁ followed by promotion with Naf produced numerous adenomas and carcinomas; their morphology resembled that of the weakly basophilic foci. Both clear-eosinophilic and weakly basophilic foci appear “spontaneously” in the liver of aging rats. Promotion of such lesions by PB-type compounds or peroxisome inducers may explain cancer formation by these non-genotoxic agents.