Yoshiichi Maeura

Simultaneous inhibition of liver carcinogenicity and enhancement of bladder carcinogenicity of N-2-fluorenylacetamide by butylated hydroxytoluene

The effect of butylated hydroxytoluene on the carcinogenicity to rats of concurrently administered N-2-fluorenylacetamide was determined. N-2-Fluorenylacetamide at 200 ppm alone in the diet produced liver neoplasms but no bladder neoplasms after 25 weeks. With simultaneous administration, 6000 ppm butylated hydroxytoluene inhibited the induction of liver neoplasms but resulted in production of bladder neoplasms. The finding that butylated hydroxytoluene inhibited hepatocarcinogenesis by N-2-fluorenylacetamide but enhanced bladder carcinogenesis demonstrates the complexity of potential effects on chemical carcinogenesis produced by modifying agents.

Induction by butylated hydroxytoluene of rat liver γ-glutamyl transpeptidase activity in comparison to expression in carcinogen-induced altered lesions

Butylated hydroxytoluene (BHT) at concentrations of 300-6000 ppm in the diet caused a dose-dependent increase in gamma-glutamyl transpeptidase (GGT) activity in normal F344 male rat liver at 18 weeks. However, the activities of glutathione S-transferases (GSTs) of rat liver cytosol were enhanced only at concentrations of 3000 or 6000 ppm BHT. Histochemically, the enhanced GGT activity was localized to hepatocytes surrounding the portal areas. Autoradiographic measurements of DNA synthesis showed that dietary BHT did not increase the level of cell proliferation and the GGT-positive hepatocytes did not exhibit different rates of DNA synthesis from those of GGT-negative cells. Feeding of the liver carcinogen N-2-fluorenylacetamide (FAA) induced foci and nodules of GGT-positive altered cells which exhibited higher rates of DNA synthesis than those of surrounding GGT-negative hepatocytes. Following iron loading, the periportal GGT-positive hepatocytes produced by BHT accumulated cellular iron, whereas the cells in FAA-induced lesions excluded iron. These results suggest that dietary BHT induces GGT activity in periportal hepatocytes without proliferation of the cells and that induction does not represent fetal expression or a preneoplastic alteration.

Abnormalities in liver iron accumulation during N-2-fluorenylacetamide hepatocarcinogenesis that are dependent or independent of continued carcinogen action.

The characteristics of liver iron accumulation were studied during N-2-fluorenylacetamide (FAA)-induced hepatocarcinogenesis in rats. After injection of iron-dextran in control rats, hepatocytes accumulated stainable iron evenly throughout hepatic lobules. During the feeding of FAA, iron accumulation was reduced in the midzonal and centrilobular regions. After FAA removal, hepatocytes in these regions again accumulated high amounts of iron. Hepatocellular altered foci induced by FAA displayed rather uniform (> 94%) iron-exclusion during FAA feeding. After FAA removal, however, iron-exclusion was lost in a fraction of the foci, while others (40-64%) remained resistant to iron accumulation. A large majority of liver neoplasms (> 93%) displayed resistance to cellular iron accumulation both during FAA feeding and after removal of FAA. Thus, iron-exclusion by liver neoplasms is carcinogen-independent and irreversible, in contrast with that of normal hepatocytes which is completely carcinogen-dependent and reversible. Altered foci appear to represent two populations: one is characterized by reversible iron-exclusion whereas the other, like neoplasms, possesses permanent iron-exclusion.