Late administration of COX-2 inhibitors minimize hepatic necrosis in chloroform induced liver injury.
Our previous studies have described the protective effects of hepatoprotective agents against liver injury elicited by chloroform even when given 24 h after the toxicant, at a time when the liver injury is taking place and rapidly developing. However, the mechanisms involved in this protection remain unknown. The cytoprotective mechanism of these hepatoprotectants such as DMSO, may be due to a dramatic shift in the production of prostaglandins that are responsible for controlling the degree of inflammatory response that can affect blood flow in the liver. In this study, NS-398, a specific COX-2 inhibitor, and indomethacin, a COX-1 and COX-2 inhibitor, were administered 24 h after chloroform dosing to determine their effect on liver injury in Sprague-Dawley rats. The extent of necrosis was evaluated by H&E staining, while injury to hepatocytes was evaluated by measuring plasma levels of alanine transaminase (ALT). Both COX inhibitors, indomethacin and NS-398, prevented an increase in (ALT) at 48 h after initial toxicant insult and attenuated further liver necrosis. No changes in cellular proliferative activity occurred in all the treatment groups, which indicates that protection from the Cyclooxygenase (COX) inhibitors did not have an effect on regeneration of cells at 32 and 48 h. These results indicate COX inhibitors provide a significant protective effect on liver cells against CHCl(3) injury and may provide further insight into therapeutic interventions against hepatotoxicants.
Begay
Carmen K
CK
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 E Mabel St, Tucson, AZ 85721-0207, USA.
Gandolfi
A Jay
AJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D002725:Chloroform / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D009336:Necrosis; D009578:Nitrobenzenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D002725:Chloroform; D000410:Alanine Transaminase; D007213:Indomethacin