Sequential alterations in
enzyme histochemical profiles and reaction of hepatocytes to rapid
iron overload were examined in male BALB/c mice during chronic,
safrole exposure. At 24 weeks after initiation of
safrole treatment, foci of
enzyme-altered hepatocytes were noted. These foci were composed of cells showing a decrease in reactivity for
glucose-6-phosphatase (Glc-6-Pase) and
succinate dehydrogenase (SDH) and an increase for
gamma-glutamyl transpeptidase (gamma-Glu-T). In control,
iron-loaded mice, the livers were intensely siderotic. In
safrole-exposed,
iron-loaded mice, foci of
iron-negative hepatocytes, varying from a few cells to a lobule in diameter, were initially noted at 24 weeks. Both
enzyme-altered and
iron-negative foci occurred in the livers of exposed mice at all time periods after 24 weeks. After 36, 52, and 75 weeks of
safrole treatment,
hepatocellular adenomas were noted with altered
enzyme histochemical profiles. Hepatocytes from
adenomas were characterized by a decreased staining for Glc-6-pase and SDH and increased staining for gamma-Glu-T and
glucose-6-phosphate dehydrogenase (Glc-6-PD). In addition, a few nodules showed a decrease in staining for
5'nucleotidase. In
iron-loaded mice, hepatocytes of
adenomas showed a decreased to negative reaction for
iron when the surrounding parenchyma was siderotic.
Hepatocellular carcinomas (HPC) occurred in livers of mice exposed to
safrole for 52-75 weeks. The cells of HPC displayed similar
enzyme histochemical reactions as cells of
adenomas. They were decreased for Glc-6-Pase and SDH activity and increased for gamma-Glu-T and Glc-6-PD. In
iron-loaded mice, the HPC cells were negative for stainable
iron. Foci,
adenomas, and HPC displayed some variability in
enzyme histochemical reactions. Variability existed between lesions as well as between cells of the same lesion.