Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats

Abstract

The effect of pravastatin, an inhibitor of p21ras isoprenylation, on hepatocarcinogenesis induced by N-nitrosomorpholine and on p21ras isoprenylation were investigated in male Sprague-Dawley rats. Rats received i.p. injections of pravastatin (10 and 20 mg kg(-1) body weight) every other day and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Visible white nodules and hepatic lesions staining positively for gamma-glutamyl transpeptidase or glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 15, pravastatin at both dosages significantly reduced the incidence, number and volume of visible white nodules. Quantitative histological analysis also showed that prolonged administration of pravastatin at both dosages resulted in significant reductions in the number and percentage area of hepatic lesions positive for gamma-glutamyl transpeptidase and glutathione-S-transferase, placental type. Administration of pravastatin also significantly decreased the amount of membrane-associated p21ras in the tumour and the labelling index of neoplastic nodules and increased the apoptoic indices of neoplastic nodules. These findings indicate that pravastatin suppresses hepatocarcinogenesis and suggest that this effect might be related to pravastatin's inhibition of p21ras isoprenylation and its subsequent inhibition of cell proliferation and induction of apoptosis in neoplastic lesions.