Modulation by Indomethacin or Prostaglandin E(2) of the Incidence of Diethylnitrosamine‐induced γ‐Glutamyltranspeptidase‐positive Foci in Rat Liver

We investigated the effect of a pretreatment with indomethacin (IMC, ip 3.6 mg/kg body weight (bw)) or dimethylprostaglandin E(2) (PGE(2), ip 10 μg/kg bw) on the incidence and development of γ‐glutamyl‐transpeptidase (GGT)‐positive foci of altered hepatocytes, scored 8 or 14 weeks after ip injection of diethylnitrosamine (DENA, 50 mg/kg bw) to rats submitted to two‐thirds hepatectomy (PH) or sham operation (Sh). IMC reduced by about 4 times the incidence of DENA‐induced GGT‐positive foci per cm(3) of liver tissue in sham‐operated as well as in two‐thirds hepatectomized rats, compared to the respective unpretreated controls. In contrast, PGE(2) pretreatment increased the incidence of DENA‐induced foci in both groups, this effect, in terms of absolute numbers of foci, being additive to that of PH alone. IMC pretreatment resulted in foci with lower average size in the Sh but not in the PH animals, whereas with PGE(2) pretreatment the mean volume of the foci was increased in the two groups of rats. At the dose used, IMC did not modify the proliferative response of hepatocytes to PH, and PGE(2) did not stimulate proliferation in the sham‐operated animals. Altogether, these results indicate that: 1, the incidence of DENA‐induced foci can be negatively modulated by interfering with the prostaglandins pathway through a mechanism that does not involve an action either on proliferative activity or on any other process that would be specific to the post‐hepatectomy regenerative state; 2, positive modulation of the incidence of DENA‐induced foci does not necessarily require stimulation of proliferation.