INHIBITION BY PIROXICAM OF OXIDATIVE DNA-DAMAGE, LIVER-CIRRHOSIS AND DEVELOPMENT OF ENZYME-ALTERED NODULES CAUSED BY A CHOLINE-DEFICIENT, L-AMINO ACID-DEFINED DIET IN RATS

Previously, we have reported that aspirin, a cyclooxygenase (COX) inhi bitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transfera se placental form (GST-P)-positive preneoplastic liver nodules, caused by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. In the present study, in order to elucidate the role of COX pathway in li ver lesion-induction by a CDAA diet, the modulatory effects of other d istinct chemical classes of COX inhibitors were examined. A long-actin g example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) a nd the short-acting ibuprofen (IBU) (at doses of 0.02, 0.04 and 0.06%) and indomethacin (IND) (at doses of 0.005 and 0.008%) were administer ed in the CDAA diet to male F344 rats, and animals were killed after 1 2 and 30 weeks. In another experiment, IND was given in drinking water at doses of 0.001, 0.002 and 0.004%. None of the inhibitors affected the development of fatty liver caused by a CDAA diet, but PIRO at dose s higher than 0.04%, strongly inhibited the development of GST-P-posit ive and neoplastic nodules as well as fibrosis, cirrhosis and formatio n of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. W ith IND, there was only a tendency for inhibition with no clear dose-d ependence. The results together with our previous findings, indicate t hat relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatoc arcinogenesis associated with a CDAA diet, although not the developmen t of a fatty liver, suggesting that an augmented COX pathway might pla y key roles in the causation of liver lesions in this model.