An experiment was performed to investigate whether, during regression of the liver
hyperplasia induced by a direct
mitogen, apoptosis differentially affects replicated and non-replicated hepatocytes. After a single dose of the direct
mitogen lead nitrate (LN), male Wistar rats were given repeated
injections of tritiated
thymidine, and were killed either 3 days (time of maximal hepatic
DNA increase) or 15 days (complete regression of the
hyperplasia) after
mitogen treatment. Determination of liver
DNA radioactivities and labelling indices (LIs) at the two time points revealed an approximately 40% loss in total liver
DNA radioactivity, a 20% decrease in the specific activity of
DNA, and a 20% reduction in the cell LI. Three days after LN administration 64% of the apoptotic bodies contained
thymidine grains in their nuclear fragments. The results indicated that apoptosis affects both hepatocytes that replicated, and those that did not replicate, the former being slightly more sensitive. A second experiment was then performed to investigate whether and to what extent different types of cell death (apoptosis versus
necrosis) influence the growth of hepatocytes initiated by a chemical
carcinogen. Male Wistar rats were given a single dose of
diethylnitrosamine, and 2 weeks thereafter either a single dose of LN, or a necrogenic dose of
carbon tetrachloride (CCl4).
Bromodeoxyuridine was next infused for 5 days, and some of the animals were killed at this time point, and others after an additional 3 weeks. Administration of CCl4 resulted in an increase in both the average size and the percentage area occupied by placental
glutathione S-transferase-positive lesions. In contrast, administration of
lead nitrate resulted in a strong reduction (50%) in the number of positive lesions with no remarkable change in the percentage area occupied by them. These differential effects occurred even though comparable LIs were observed in rats treated with the two agents. The results suggest that
lead nitrate leads to a loss of initiated hepatocytes, due to the apoptosis that occurs during regression of the LN-induced
hyperplasia.