INHIBITION BY THE CALMODULIN ANTAGONIST TRIFLUOPERAZINE OF EXPERIMENTAL HEPATOCARCINOGENESIS INDUCED BY N-NITROSOMORPHOLINE IN SPRAGUE-DAWLEY RATS

The effect of the calmodulin antagonist trifluoperazine on hepatocarci nogenesis induced by N-mitrosomorpholine (NNM) and on the ornithine de carboxylase (ODC) activity and labeling index of the liver were invest igated in male Sprague-Dawley rats. Rats were given drinking water con taining NNM for 8 weeks, and from the beginning of the experiment, rec eived s.c. injections of 15 or 30 mg/kg body weight of trifluoperazine in depot form every other day until the end of the experiment. Preneo plastic and neoplastic lesions staining positively for glutathione-S-t ransferase, placental type (GST-P) were examined histochemically. In w eek 16, quantitative histological analysis showed that prolonged admin istration of 30 mg but not 15 mg/kg body weight of trifluoperazine res ulted in significant reductions in the number and percentage area of G ST-P-positive hepatic lesions. Trifluoperazine also caused significant decreases in the ODC activity of the liver and in the labeling indice s of enzyme-altered lesions and their adjacent hepatocytes. These find ings indicate that trifluoperazine inhibits carcinogenesis and suggest that this effect may be closely related to its effect in inhibiting O DC activity and cell proliferation in the enzyme-altered lesions and t heir adjacent liver.