Effect of 4-acetylaminofluorene and other tumour promoters on hepatocellular growth and binucleation

Abstract

The complete liver carcinogen 2-acetylaminofluorene (2-AAF) promoted the outgrowth of large neoplastic liver nodules and hepatocellular carcinomas in diethylnitrosamine-treated rats. 2-AAF did not alter the overall proliferative activity of normal hepatocytes, but suppressed binucleation and induced, on a long-term basis, an increase in proliferative activity and in the fraction of diploid hepatocytes relative to control animals. The analogue 4-acetylaminofluorene (4-AAF) was much less effective than 2-AAF as a promoter of large nodules and carcinomas, but promoted the outgrowth of medium-sized nodules (1 < 2.5 mm). While 2-AAF specifically stimulated the growth of cells in enzyme-altered foci, the cells responding to 4-AAF were more randomly distributed throughout the liver tissue. In contrast to 2-AAF, 4-AAF strongly stimulated the growth (DNA synthesis) of normal hepatocytes, but like 2-AAF it suppressed binucleation and caused a long-term increase in the proliferative activity and in the fraction of diploid hepatocytes. Other liver tumour promoters (cyproterone acetate, alpha-hexachlorocyclohexane, methylclofenapate) likewise stimulated the growth and suppressed the binucleation of normal hepatocytes. All hepatocellular ploidy classes were affected virtually equally by mitogenic stimulation, but at low proliferation rates the mononuclear cells were more proliferative than the binuclear cells. Since this difference could be eliminated by increasing the mitogen dose, it would seem that mononuclear cells may be somewhat more sensitive towards mitogens than binuclear cells. In contrast to previously reported results [Styles et al. (1990) Carcinogenesis, 11, 1149-1152], methylclofenapate was not found to specifically stimulate binuclear hepatocytes. Our results indicate that liver tumour promoters in general tend to induce a non-binucleating, non-polyploidizing hepatocellular growth pattern, similar to that observed during liver regeneration. 4-AAF is confirmed to be, at best, a very weak promoter of liver carcinogenesis, but appears to be an effective promoter of benign tumours.

Characterization of Multinuclear Hepatocytes Induced in Rats by Mitemcinal (GM-611), an Erythromycin Derivative

“…Several studies indicate that the type of shift is dependent on the cause (Seglen 1997). Although the ploidy was not considered in the present study, the sharp shift toward mononuclear cells was thought to be similar to shifts seen in regenerating rat liver after partial hepatectomy (Auvigne et al 2002;Frederiks et al 1990;Gerlyng et al 1993;Melchiorri et al 1993;Seglen 1997;Wheatley 1972), which is similar to shifts with certain drugs (Gerlyng et al 1994;Seglen 1997).…”

“…The binuclear cell population is approximately 30%–40% in normal rat liver (Engelmann et al 1981; Fujii et al 2004; Gerlyng et al 1993; Mossin et al 1994; Seglen 1997; Wheatley 1972). Although the mechanisms are unclear, the ratio of mono- and binuclear hepatocytes is known to change with age (Engelmann et al 1981; Gerlyng et al 1993; Seglen 1997; Wheatley 1972), partial hepatectomy (Auvigne et al 2002; Frederiks et al 1990; Gerlyng et al 1993; Melchiorri et al 1993; Seglen 1997; Wheatley 1972), endocrine status (Lamers 1985; Mossin et al 1994; Wheatley 1972), and certain hepatomitogenic and hepatocarcinogenic drugs (Auvigne et al 2002; Gerlyng et al 1994; Kostka et al 1994; Kostka et al 2000; Melchiorri et al 1993; Palut et al 1992; Seglen 1997).…”

Comparison of mitosis in binucleated and mononucleated newt cardiac myocytes

“…Because of the more variable results of mitosis of binucleated myocytes than of mononucleated myocytes, it would appear that mitosis in binucleated myocytes is less controlled and perhaps is indicative of a more aberrant process that may terminate further proliferative potential. This has been suggested in the case of hepatocyte binucleation (Gerlyng et al, 1992(Gerlyng et al, , 1994Mossin et al, 1994).…”

Elevated Interferon Gamma Signaling Contributes to Impaired Regeneration in the Aged Liver

“…Binucleation and polyploidization are irreversible differentiation events, which have been shown to negatively effect the growth potential of the liver. The diploid hepatocytes show higher proliferative activity than polyploid cells after PH or treatment with mitogenic compounds (43,44). Reduced telomere length is one of the critical factors contributing to cellular aging and replicative senescence (45,46).…”