Effect of acetaminophen on hepatic content and biliary efflux of glutathione disulfide in mice.
The increased expiration of ethane and pentane by mice treated with hepatotoxic doses of acetaminophen suggests the possibility of oxidant mechanisms associated with the necrosis. However, studies in rats are not consistent with oxidant stress mechanisms causing the damage, because acetaminophen given to rats does not increase GSSG efflux, a sensitive index of intrahepatic oxidant stress. To compare the extent of oxidant stress generated by acetaminophen in mice versus rats, hepatic content and biliary efflux of GSSG and GSH in mice have been examined. Bile was collected from anesthetized male ICR mice before and after intraperitoneal administration of acetaminophen (325 mg/kg, 2.15 mmol/kg), t-butyl hydroperoxide (TBHP) (1.5 mmol/kg), diethyl maleate (400 mg/kg, 2.33 mmol/kg, in corn oil) or saline (control) and GSH and GSSG were measured by the enzymatic recycling method of Tietze. An increase in biliary GSSG efflux was produced by t-butyl hydroperoxide, but not by the other agents. Biliary GSH/GSSG ratios decreased in acetaminophen-treated animals, presumably reflecting the marked depletion of hepatic GSH, since a similar decrease was observed with non-hepatotoxic doses of diethyl maleate. The failure of acetaminophen to increase the hepatic content or biliary efflux of GSSG in ICR mice is not consistent with the view that oxidant stress mechanisms cause the damage, despite the increases in alkanes expired after acetaminophen administration in this specific animal model.
Smith
C V
CV
Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030.
Jaeschke
H
H
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000187:drug effects*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D019803:Glutathione Disulfide; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR
D008298:Maleates; D000082:Acetaminophen; C014476:diethyl maleate; D005978:Glutathione; D019803:Glutathione Disulfide