Drug-induced lipid peroxidation in mice--V. Ethane production and glutathione release in the isolated liver upon perfusion with acetaminophen.
Isolated liver from phenobarbital-induced male mice was perfused using infusions of cytochrome c pulses as quality control of the system. Livers spontaneously evolved 1.1 pmoles ethane g-1 liver min-1, exogenous pentane disappeared with 0.6 pmoles g-1 min-1. Infusion of 0.26 mmoles/l. FeCl2 led to immediate ethane production followed later on by lactate dehydrogenase release from the liver. Infusion of acetaminophen resulted in hepatic ethane production at drug concentrations greater than 0.1 mmoles/l. A maximum effect was observed at 2 mmoles/l. of acetaminophen infused while higher concentrations, up to 10 mmoles/l. delayed ethane release although they enhanced the rate of glutathione depletion. This glutathione efflux decreased from 12 nmoles/g-1 min-1 observed after perfusion of medium alone to 2.9 nmoles/g-1 min-1 when AAP was infused. The slope of the pseudo first order depletion kinetics depended on the acetaminophen concentrations. This glutathione release represents the perisinusoidal portion of the total efflux measured here independently from the biliary secretion. The results show that in agreement with the in vivo findings acute intoxication of liver with high doses of this drug lead to lipid peroxidation, while in vitro an apparent antioxidative effect was measured. The implications for drug screening are probably important.
D000082:Acetaminophen / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004980:Ethane / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D010477:Perfusion
D008054:Lipid Peroxides; D000082:Acetaminophen; D005978:Glutathione; D004980:Ethane