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 prostacyclinthromboxane 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, prostacylcin 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, prostacylcin and OKY 1581 were without activity.
Prostacyclin treatment can prevent acetaminopheninduced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.
Acetaminophen (paracetamol, N-acetyl-p-aminophenol) is a mild analgesic and antipyretic drug developed in the last century (1). Hepatic injury by acetaminophen as a result of therapeutic use is almost absent. However, the drug causes massive liver necrosis when consumed in large quantities, generally as a suicidally motivated overdose (2, 3). There is evidence to suggest that the hepatotoxicity is related to the cytochrome P-450-linked metabolism of the drug to one or more reactive species, which may interact with hepatocyte membranes to produce necrosis (4-6). Such interactions only occur when hepatic levels of reduced glutathione have