The possible mechanism(s) responsible for the different effects exerted by proliferative stimuli of different nature on the appearance of
enzyme-altered hepatic foci, were investigated in male Wistar rats. Rats given an initiating dose of
diethylnitrosamine (150 mg/kg
body weight) were fed a diet containing 0.03%
acetylaminofluorene for 2 weeks. Between the first and the second week, cell proliferation was induced by a proliferative stimulus of compensatory type (partial
hepatectomy) or by a direct mitogenic stimulus (
lead nitrate, 100 mumol/kg). The effect of the two different proliferative stimuli on the appearance of gamma-glutamyl
transferase-positive foci was monitored by killing the rats for examination at 1, 2, 3, 5, and 6 days after the induction of cell proliferation. The results indicate that while
enzyme-altered hepatocytes can be observed as early as 3 days after partial
hepatectomy and are characterized by a rapid growth, direct
hyperplasia did not exert any effect on the growth capacity of initiated cells. No effect of
lead nitrate-induced
hyperplasia was observed following three administrations of the
mitogen. When platelet-poor plasma taken from animals exposed to the different proliferative stimuli was tested in primary cultures of hepatocytes, it was found that it induced a significant increase in the labeling index of normal hepatocytes. However, while serum taken 6 days after partial
hepatectomy was still able to induce a significant increase in the labeling index, platelet-poor plasma from lead-treated rats had lost part of its effect at 5 days
after treatment. The inability of direct
hyperplasia to stimulate the development of
enzyme-altered hepatic foci was not unique to
lead nitrate since the same phenomenon was observed when three other hepatomitogens,
nafenopin,
cyproterone acetate, and
ethylene dibromide, were used.