Hepatic lipid peroxidation: caused by acute drug intoxication, prevented by liposomal glutathione.
Acute intoxication of mice with high doses of paracetamol (acetaminophen, 4-hydroxyacetanilide) led to a dose-dependent lipid peroxidation (LPO) measured in vivo by ethane exhalation and in vitro by malondialdehyde formation and glutathione depletion. Induction of microsomal enzymes enhanced LPO, inhibition of the monooxygenase systems totally suppressed it. Other drugs activated in phase I, i.e., furosemide, ethylmorphine or aminopyrine acted similarly if the phase II conjugation to glutathione was paralysed by glutathione depletion with diethylmaleate. The concept of lipid peroxidation being an early causal event in hepatocellular destruction was further examined experimentally: 1) Animals with alimentary selenium deficiency lacking liver selenium-dependent glutathione peroxidase activity were much more susceptible to paracetamol-induced liver necrosis and LPO. 2) Normally fed animals were totally resistant when pretreated by intravenous liposomally entrapped glutathione. Administration of free glutathione led to a similar increase in hepatic glutathione content but the animals were much less protected. 3) Isolated perfused mouse liver released quantitatively similar amounts of ethane upon perfusion of paracetamol. The hydrocarbon evolution was reversible and preceded cell disintegration monitored by release of lactate dehydrogenase. 4) The few human data available indicate that man has a much lower activity of hydroperoxide metabolizing enzymes and much less glutathione. The results suggest an involvement of lipid peroxidation in acute chemical primary lesions. A general pathogenic mechanism for liver injury cannot be derived at present from the data available.
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology*; D006838:Hydrocarbons / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism*; D008081:Liposomes / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction
D006838:Hydrocarbons; D008054:Lipid Peroxides; D008081:Liposomes; D000082:Acetaminophen; D005978:Glutathione