Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse.
The effect of prostacyclin on acetaminophen-induced liver injury has been investigated in the mouse. Two structurally unrelated thromboxane synthetase inhibitors, OKY 1581 and benzyl imidazole, were also examined in order to investigate the role of the prostacyclin-thromboxane balance in the development of hepatic lesions. Whereas prostacyclin or OKY 1581 given shortly after acetaminophen prevented mortality and reduced liver necrosis, as assessed by serum ALT activity and histology, benzyl imidazole was only effective if given prior to acetaminophen. Acetaminophen overdose resulted in an enhanced prostaglandin and thromboxane generation by liver homogenates. While OKY 1581 inhibited thromboxane production by the liver homogenates, prostacyclin synthesis was increased. Pretreatment with the cyclooxygenase inhibitor indomethacin blocked both the increase in prostacyclin generation and the protective effect of OKY 1581. Benzyl imidazole inhibited the synthesis of thromboxane but did not enhance prostacyclin production. In addition, the protective effect of benzyl imidazole was unaltered by indomethacin pretreatment. Furthermore, whereas benzyl imidazole interfered with hepatic drug metabolism, as assessed by prolongation of the pentobarbitone sleeping time, prostacyclin and OKY 1581 were without activity. Prostacyclin treatment can prevent acetaminophen-induced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.
Guarner
F
F
Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Boughton-Smith
N K
NK
Blackwell
G J
GJ
Moncada
S
S
D000082:Acetaminophen / Q000506:poisoning*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D011464:Epoprostenol / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010424:Pentobarbital / Q000494:pharmacology; D011466:Prostanoic Acids / Q000096:biosynthesis; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D011466:Prostanoic Acids; D000082:Acetaminophen; D011464:Epoprostenol; D000410:Alanine Transaminase; D010424:Pentobarbital