Increased susceptibility of livers of aged F344/NCr rats to the effects of phenobarbital on the incidence, morphology, and histochemistry of hepatocellular foci and neoplasms.

Aged (875 days old) and young 42 days old) male F344/NCr rats were given sodium phenobarbital (PB) in drinking water for periods up to 233 days. Groups of aged rats were killed at 30 or 60 days or allowed to live their normal life-span, and the cause of death was determined. Young rats killed after 30, 60, and 150 days of PB exposure. Hepatocellular foci were classified into basophilic, eosinophilic, or vacuolated types according to morphologic appearance of the hepatocyte cytoplasm and were characterized by histochemical methods for the presence of gamma-glutamyl transpeptidase (GGT). The most common contributing causes of death for rats in both groups were large granular lymphocyte (LGL) leukemia and pituitary tumors. PB decreased the incidence of LGL leukemia but increased the incidence and multiplicity of hepatocellular GGT-positive foci, eosinophilic foci, and eosinophilic hepatocellular adenomas. GGT-positive eosinophilic foci increased in diameter and volume, but not in number, after appearing early in the experiment. Hepatocellular basophilic foci and neoplasms in aged control rats were usually GGT-negative and did not appear to respond to dietary PB. GGT-positive foci were seen in aged control rat livers and were composed of vacuolated amphophilic hepatocytes that differed morphologically from hepatocytes in naturally occurring liver tumors. Young rats given PB had few GGT-positive foci by 150 days on test. Aged rat livers were thus more sensitive to the effects of PB than were livers of young rats.