title: Different effects of regenerative and direct mitogenic stimuli on the growth of initiated cells in the resistant hepatocyte model.
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.
authors.affiliation: Istituto di Patologia Sperimentale, University of Cagliari, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Coni
authors.forename: G
authors.initials: G
authors.lastname: Pichiri-Coni
authors.forename: M
authors.initials: M
authors.lastname: Curto
authors.forename: G
authors.initials: G
authors.lastname: Simbula
authors.forename: L
authors.initials: L
authors.lastname: Giacomini
authors.forename: D S
authors.initials: DS
authors.lastname: Sarma
authors.forename: G M
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: A
authors.initials: A
authors.lastname: Columbano
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004052:Diethylnitrosamine; D006498:Hepatectomy; D007854:Lead / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D008934:Mitogens / Q000494:pharmacology*; D009566:Nitrates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D005723:gamma-Glutamyltransferase / Q000032:analysis
chemical_list: D008934:Mitogens; D009566:Nitrates; D007854:Lead; D004052:Diethylnitrosamine; C017461:lead nitrate; D004247:DNA; D015073:2-Acetylaminofluorene; D005723:gamma-Glutamyltransferase