AIM: To investigate the role of oxidative injury in pancreatitis-induced hepatic damage and the effect of antioxidant agents such as melatonin, ascorbic acid and N-acetyl cysteine on caerulein-induced pancreatitis and associated liver injury in rats.METHODS: Thirty-eight female Wistar rats were used.Acute pancreatitis (AP) was induced by two i.p. injections of caerulein at 2-h intervals (at a total dose of 100μg/kg b.wt). The other two groups received additional melatonin (20 mg/kg b.wt) or an antioxidant mixture containing L(+)-ascorbic acid (14.3 mg/kb.wt.) and N-acetyl cysteine (181 mg/kg b.wt.) i.p. shortly before each injection of caerulein. The rats were sacrificed by decapitation 12 h after the last injection of caerulein.Pancreatic and hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as malondialdehyde (MDA) and changes in tissue antioxidant enzyme levels, catalase (CAT) and glutathione peroxidase (GPx). Histopathological examination was performed using scoring systems.RESULTS: The degree of hepatic cell degeneration, intracellular vacuolization, vascular congestion, sinusoidal dilatation and inflammatory infiltration showed a significant difference between caerulein and caerulein + melatonin (P= 0.001), and careulein and caerulein+ L(+)-ascorbic acid +N-acetyl cysteine groups (P= 0.002). The degree of aciner cell degeneration, pancreatic edema,intracellular vacuolization and inflammatory infiltration showed a significant difference between caerulein and caerulein+ melatonin (P=0.004), and careulein and caerulein + L(+)-ascorbic acid +N-acetyl cysteine groups (P= 0.002). Caerulein-induced pancreatic and liver damage was accompanied with a significant increase in tissue MDA levels (P= 0.01, P= 0.003, respectively) whereas a significant decrease in CAT (P=0.002, P=0.003,respectively) and GPx activities (P= 0.002, P=0.03, respectively). Melatonin and L(+)-ascorbic acid+N-acetyl cysteine administration significantly decreased MDA levels in pancreas (P= 0.03, P=0.002, respectively) and liver (P=0.007, P=0.01, respectively). Administration of these agents increased pancreatic and hepatic CAT and GPx activities. Melatonin significantly increased pancreatic and hepatic CAT (P= 0.002, P= 0.001, respectively)and GPx activities (P=0.002, P= 0.001). Additionally,L(+)-ascorbic acid+N-acetyl cysteine significantly increased pancreatic GPx (P= 0.002) and hepatic CAT and GPx activities (P= 0.001, P= 0.007, respectively)CONCLUSION: Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage. Antioxidant agents such as melatonin and ascorbic acid +N-acetyl cysteine, are capable of limiting pancreatic and hepatic damage produced during AP via restoring tissue antioxidant enzyme activities.