Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A₂ inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats

Abstract

Effects of inhibitors of arachidonic acid (AA) metabolism on the development of fatty liver, cirrhosis, glutathione-S-transferase placental form (GST-P)-positive nodules and the generation of 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid-reactive substances (TBARS), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male Fischer 344 rats by feeding CDAA diets supplemented with the inhibitors for 12 and 30 weeks. Acetylsalicylic acid (ASA) (at doses of 0.1 and 0.2%) and p-bromophenacylbromide (BPB) (0.1 and 0.2%) were used as inhibitors of, respectively, cyclo-oxygenase and phospholipase A2, and quercetin (QU) (0.75 and 1.5%) and nordihydroguaiaretic acid (NDGA) (0.1 and 0.2%) as inhibitors of lipoxygenase. None of the inhibitors affected the development of fatty liver caused by the CDAA diet. ASA at a doe of 0.2% almost completely prevented the appearance of cirrhosis, GST-P-positive nodules, 8-OHdG and TBARS in seven out of 11 (63.7%) rats. BPB at a dose of 0.2% also exerted inhibitory effects on all of these lesions but to a lesser extent than ASA. QU and NDGA exerted inhibitory effects limited to the GST-P-positive nodule case. The results indicate that a perturbed AA metabolism, particularly of the cyclo-oxygenase pathway, derived secondarily from depletion of labile methyl groups or phosphatidylcholine, might play key roles in the cirrhosis, hepatocarcinogenesis and oxidative stress caused by a CDAA diet. The results also indicated a possible involvement of the lipoxygenase pathway in hepatocarcinogenic processes.

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

“…Our findings are consistent with previous studies showing increased expression and enhanced formation of COX-2-and 5-LO-derived products in patients with chronic liver disease and progressive fibrosis (Uemura et al, 1994;Cheng et al, 2002a;Mohammed et al, 2004;Nú ñ ez et al, 2004) and in experimental models including CCl 4 -induced liver injury, alcoholic liver disease, and diet-induced steatohepatitis (Nanji et al, 1997 (Endoh et al, 1996;Yamamoto et al, 2003;Planagumà et al, 2005;Titos et al, 2005). …”

Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress

“…We estimated 8-OHdG levels in the DEN-alone and the DEN-high ORPH groups, but not in the DEN-low ORPH group. Since 8-OHdG level is correlated with the TBARS level (Endoh et al, 1996), we considered that the 8-OHdG level in the DEN-low ORPH group may not show a remarkable increase as compared with the DENalone group, taking into account the data on TBARS in the DEN-low ORPH group.…”

Down-Regulation of a Hepatic Transporter Multidrug Resistance-Associated Protein 2 Is Involved in Alteration of Pharmacokinetics of Glycyrrhizin and Its Metabolites in a Rat Model of Chronic Liver Injury

“…The CDAA and control, choline-supplemented L-amino-defined (CSAA) diets were obtained from Dyets, Inc. (Bethlehem, PA). The compositions of these diets were previously described (Nakae et al, 1992;Endoh et al, 1996;Sakaida et al, 1996). Biochemical Analysis.…”