title: 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.
abstract: Previously, we have reported that aspirin, a cyclooxygenase (COX) inhibitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transferase 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 liver lesion-induction by a CDAA diet, the modulatory effects of other distinct chemical classes of COX inhibitors were examined. A long-acting example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) and 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 administered in the CDAA diet to male F344 rats, and animals were killed after 12 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 doses higher than 0.04%, strongly inhibited the development of GST-P-positive and neoplastic nodules as well as fibrosis, cirrhosis and formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. With IND, there was only a tendency for inhibition with no clear dose-dependence. The results together with our previous findings, indicate that relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatocarcinogenesis associated with a CDAA diet, although not the development of a fatty liver, suggesting that an augmented COX pathway might play key roles in the causation of liver lesions in this model.
authors.affiliation: Department of Oncological Pathology, Cancer Center, Nara Medical University, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Denda
authors.forename: T
authors.initials: T
authors.lastname: Endoh
authors.forename: W
authors.initials: W
authors.lastname: Kitayama
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.forename: O
authors.initials: O
authors.lastname: Noguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: H
authors.initials: H
authors.lastname: Akai
authors.forename: E
authors.initials: E
authors.lastname: Okajima
authors.forename: T
authors.initials: T
authors.lastname: Tsujiuchi
authors.forename: M
authors.initials: M
authors.lastname: Tsutsumi
authors.forename: D
authors.initials: D
authors.lastname: Nakae
authors.forename: Y
authors.initials: Y
authors.lastname: Konishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002794:Choline / Q000008:administration & dosage; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004326:Drinking / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005526:Food, Formulated; D005982:Glutathione Transferase / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008297:Male; D010894:Piroxicam / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D010894:Piroxicam; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D002794:Choline; D007052:Ibuprofen; D007213:Indomethacin