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
A. Denda et al., 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, Carcinogenesis, 18(10), 1997, pp. 1921-1930
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.