Interaction between nitric oxide synthase and cyclooxygenase in the development of acetaminophen-induced hepatotoxicity -

Objective: Ingestion of high doses of acetaminophen (paracetamol, N-acetyl- p -aminophenol; APAP) is known to cause toxic hepatitis. This study aimed to examine the interrelationship between nitric oxide synthase (NOS) and cyclooxygenase (COX) systems in the course of APAP-induced hepatotoxicity in the rat. Materials and Methods: Sprague-Dawley rats were injected intra-peritoneally with APAP (500 mg/kg) alone or along with the non-selective NOS inhibitor N ω -Nitro-L-arginine methyl ester hydrochloride (L-NAME; 20 mg/kg), iNOS inhibitor aminoguanidine (AG; 8 mg/kg), non-selective COX inhibitor indomethacin (INDO; 5 mg/kg), selective COX-2 inhibitor nimesulide (NIM; 10 mg/kg) and selective COX-1 inhibitor ketorolac (KET; 5 mg/kg). 24 h after APAP administration, the liver and blood samples were collected for biochemical and morphological evaluations. Results: AG and KET prevented the increase in liver malondialdehyde levels due to APAP toxicity. Decreased liver glutathione in APAP group was prevented by all treatments except NIM. Stimulated liver myeloperoxidase activity in APAP group was attenuated by all treatments except INDO and NIM. Elevation of liver chemiluminescence, nuclear factor- κ B expression and serum alanine transferase level due to APAP overdose were also suppressed by all treatments. Conclusions: NOS and COX pathways interact in the development of hepatotoxicity due to APAP overdose.