Different effects of regenerative and direct mitogenic stimuli on the growth of initiated cells in the resistant hepatocyte model

CONI, PIERPAOLO;PICHIRI CONI G;CURTO M;SIMBULA, GABRIELLA;GIACOMINI L;SARMA DS;LEDDA, GIOVANNA MARIA;COLUMBANO, AMEDEO

1993-01-01

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Abstract

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.