INHIBITION BY PHENYL N-TERT-BUTYL NITRONE OF EARLY PHASE CARCINOGENESIS IN THE LIVERS OF RATS FED A CHOLINE-DEFICIENT, L-AMINO ACID-DEFINEDDIET

Male Wister rats were fed a choline-deficient, L-amino acid-defined (C DAA) diet alone or in combination with a nitrone-based free radical tr apping agent, phenyl N-tert-butyl nitrone (PBN) in the drinking water at the concentrations of 0.013, 0.065, and 0.130% for 12 weeks. PBN in hibited the changes that are normally induced in the livers of rats by the CDAA diet feeding, i.e., development of putative preneoplastic le sions, proliferation of connective tissue, reduction of glutathione S- transferase activity, formation of 8-hydroxyguanine in DNA and an incr ease in inducible cyclo-oxygenase (COX2) activity. PBN, however, did n ot prevent the increases in the COX2 mRNA or protein le,els brought on by the CDAA diet. These results indicate that the loss of glutathione S-transferase activity and COX2 induction may play significant roles in rat liver carcinogenesis by the CDAA diet and that PBN prevents neo plasia not only by its radical scavenging activity but also by inhibit ing COX2 activity at the catalytic level.