Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the liver injury caused by ischaemia-reperfusion: a comparison with radical scavengers.
1. Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA which are caused by reactive oxygen species (ROS) and peroxynitrite. Excessive activation of PARS may contribute to the hepatocyte injury caused by ROS in vitro and inhibitors of PARS activity reduce the degree of reperfusion injury of the heart, skeletal muscle and brain in vivo. Here we compared the effects of various inhibitors of the activity of PARS with those of deferoxamine (an iron chelator which prevents the generation of hydroxyl radicals) and tiron (an intracellular scavenger of superoxide anion) on the degree of hepatic injury caused by ischaemia and reperfusion of the liver in the anaesthetized rat or rabbit. 2. In the rat, ischaemia (30 or 60 min) and reperfusion (120 min) of the liver resulted in significant increases in the serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) indicating the development of liver injury. Intravenous administration of the PARS inhibitors 3-aminobenzamide (3-AB, 10 mg kg(-1) or 30 mg kg(-1)), 1,5-dihydroxyisoquinoline (ISO, 1 mg kg(-1)) or 4-amino-1,8-naphthalimide (4-AN, 3 mg kg(-1)) before reperfusion did not reduce the degree of liver injury caused by ischaemia-reperfusion. 3. In contrast to the PARS inhibitors, deferoxamine (40 mg kg(-1)) or tiron (300 mg kg(-1)) significantly attenuated the rise in the serum levels of AST and ALT caused by ischaemia-reperfusion of the liver of the rat. 4. In the rabbit, the degree of liver injury caused by ischaemia (60 min) and reperfusion (120 min) was also not affected by 3-AB (10 mg kg(-1)) or ISO (1 mg kg(-1)). 5. These results support the view that the generation of oxygen-derived free radicals mediates the liver injury associated with reperfusion of the ischaemic liver by mechanism(s) which are independent of the activation of PARS.
William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry.
J
J
Bowes
C
C
Thiemermann
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008099:Liver / Q000473:pathology*; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D000067856:Poly(ADP-ribose) Polymerase Inhibitors