E.M.Jack, W.Staubli, F.Waechter, P.Bentley, J.Suter,

Ultrastructural changes were investigated and quantified, using a stereological approach, in early gamma-glutamyl-transpeptidase (GGT)-positive focal lesions, induced in the rat liver by treatment with a single initiating dose of diethylnitrosamine (DENA) followed by promotion with phenobarbitone (PB) for 30 weeks. Within the extra-hepato-cyte environment of focal tissue, the mean volume occupied by Ito cells was markedly decreased, whilst that occupied by endothelial and Kupffer cells was increased, when compared to unlnvolved tissue from the same rat livers. The bile canalkuli were dilated, but no significant differences in the mean volume occupied by the sinusoidal and Disse spaces were noted. In focal hepatocytes there was a striking overpro-duction of lipid droplets and proliferation of smooth endo-plasmlc retkulum (sER). Whorls of concentrically arranged, parallel ER membranes were found only in the hepatocytes of preneoplastk foci, in association with the proliferated sER, and never in the surrounding, uninvolved tissue. The increase hi mean volume of the sER, lipid droplet and cytoplasmk matrix compartments, together with the appearance of whorls, were the major contributing factors to the marked hypertrophy seen in focal hepatocytes. The mean volume of the rough endoplasmic reticulum, mitochondrial, lysosomal, peroxisomal and nuclear compartments per hepatocyte also increased, but contributed to a lesser extent to the cellular hypertrophy. It is speculated that whorls may be structural adaptations, resulting from a possible alteration in the normal feedback control of cholesterol synthesis, for the production of sterols and the biogenesis of sER in eosinophilk-ty pe focal cells. The significance of changes observed in focal tissue, and the high biological variation noted between foci, is discussed in relation to the hepatocarcinogenic process