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.

Celecoxib, a selective cyclooxygenase-2 inhibitor, lowers plasma cholesterol and attenuates hepatic lipid peroxidation during carbon-tetrachloride–associated hepatotoxicity in rats

“…Horrillo et al (2007) reported on the protective effect of SC-236, a selective COX-2 inhibitor, against liver inflammation and fibrosis and proposed that the COX pathway of the arachidonic acid cascade might represent a potential target for therapy. Similar observations have also been reported by some other investigators (Yamamoto et al, 2003;Denda et al, 1997;Tu et al, 2007;Planaguma et al, 2005). There are other studies, however, that have reported exacerbation in fibrogenesis after COX-2 inhibition (Hui et al, 2006;Reilly et al, 2001;Yu et al, 2008).…”

“…Although the effects of treatment with COX-2 inhibitors on the progression of liver fibrosis have been investigated in various experimental models, results from these studies, however, are controversial. Though some investigators reported exacerbation (Hui et al, 2006;Reilly et al, 2001;Yu et al, 2008), others observed amelioration (Yamamoto et al, 2003;Denda et al, 1997;Tu et al, 2007;Planaguma et al, 2005) in fibrogenesis after COX-2 treatment. Overexpression of COX-2 messenger RNA has been demonstrated in rats with CCl 4 -induced cirrhosis, and indomethacin (a nonselective inhibitor of COX) decreased the hyperresponse to vasoconstrictors and increased resistance to portal flow-the primary factor in the pathophysiology of portal hypertension in cirrhotic livers (Graupera et al, 2003).…”

Distribution of constitutive (COX-1) and inducible (COX-2) cyclooxygenase in postviral human liver cirrhosis: a possible role for COX-2 in the pathogenesis of liver cirrhosis

“…Thus, in liver cirrhosis, COX-2 could contribute to the pathogenesis of HCC by increasing necroinflammatory activity and promoting proliferation, 32 enhancing angiogenesis, 39 and inhibiting apoptosis. [40][41][42] In human liver cirrhosis and carbon tetrachloride (CCl 4 ) induced liver cirrhosis in rats, there is increased renal synthesis of vasodilator PGs, which counteract the actions of endogenous vasoconstrictors such as angiotensin II, norepinephrine, and antidiuretic hormone on the renal vascular and tubular systems. 43 Therefore, administration of NSAIDs in cirrhosis could induce renal failure by inhibiting renal COX and blocking PG synthesis.…”

Non-steroidal anti-inflammatory drugs and bladder cancer prevention

“…Experimental data are supportive of this hypothesis and also suggest that NSAIDs might provide protection against cancers of the mammary gland, skin and liver as well as the urinary bladder (Moon et al, 1992;Kelloff et al, 1994;Giardiello et al, 1995;Denda et al, 1997). The preventive mechanisms remain to be elucidated in detail but have been postulated to involve their inhibition of cyclooxygenase (COX), thereby inhibiting production of prostaglandins which influence tumour growth through both by stimulating cell proliferation and by disturbing immunological surveillance (Marnett, 1992;Giardiello et al, 1995;Lupulescu, 1996).…”