SUPPRESSION BY PRAVASTATIN, AN INHIBITOR OF P21(RAS) ISOPRENYLATION, OF HEPATOCARCINOGENESIS INDUCED BY N-NITROSOMORPHOLINE IN SPRAGUE-DAWLEY RATS

The effect of pravastatin, an inhibitor of p21(ras) isoprenylation, on hepatocarcinogenesis induced by N-nitrosomorpholine and on p21(ras) i soprenylation were investigated in male Sprague-Dawley rats. Rats rece ived 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. Vesible whi te nodules and hepatic lesions staining positively fur gamma-glutamyl transpeptidase or glutathione-S-transferase, placental type, were exam ined macroscopically or histochemically. In week 15, pravastatin at bo th dosages significantly reduced the incidence, number and volume of v isible white nodules. Quantitative histological analysis also showed t hat prolonged administration of pravastatin at both dosages resulted i n significant reductions in the number and percentage area of hepatic lesions positive for gamma-glutamyl transpeptidase and glutathione-S-t ransferase, placental type. Administration of pravastatin also signifi cantly decreased the amount of membrane-associated p21(ras) in the tum our and the labelling index of neoplastic nodules and increased the ap optoic indices of neoplastic nodules. These findings indicate that pra vastatin suppresses hepatocarcinogenesis and suggest that this effect might be related to pravastatin's inhibition of p21(ras) isoprenylatio n and its subsequent inhibition of cell proliferation and induction of apoptosis in neoplastic lesions.