Lipid Peroxidation In Mice Research Articles

Drug-induced lipid peroxidation in mice—II: Protection against paracetamol-induced liver necrosis by intravenous liposomally entrapped glutathione

If injected intravenously 2 hr before the drug, a dose of more than 175 mg/kg body weight glutathione (0.57 mmol/kg) protected male mice from acute liver necrosis induced by intraperitoneal administration of mg/kg (2.65 mmol/kg) paracetamol. Soluble glutathione yielded a limited, and liposomally entrapped glutathione an optimal dose-dependent protective effect against drug-induced lipid peroxidation (as measured by in vivo ethane exhalation) liver necrosis (assessed by serum transaminases) and hepatic glutathione depletion (determined post mortem). N-Acetylcysteine solution had no effect in this model.

Drug-induced lipid peroxidation in mice—III: Glutathione content of liver, kidney and spleen after intravenous administration of free and liposomally entrapped glutathione

The half-life of extracellular glutathione was found to be 1.9 min in fed mice with a hepatic glutathione content of 44 ± 10 nmol glutathione per mg protein. It was 4.9 min in animals that had been fed for 48 hr a liquid sucrose diet resulting in a decreased hepatic glutathione of 25 ± 7 nmol/mg. A single intravenous injection of 16.2 μmol liposomally entrapped glutathione led to an increase in hepatic glutathione to 45 nmol/mg in the sucrose-fed mice after 2 hr and had no effect in the fed group. The spleen glutathione content reached a maximum at 30 min after injection in both groups. The maximum uptake into liver was 21% of the applied dose, into the spleen 7% and into the kidneys 2.4%. Injection of glutathione in solution led to a similar increase of hepatic glutathione as observed with GSH- containing liposomes, while liposomes filled with the constituent amino acids had only a marginal effect. The spleen took up only liposomal GSH. In contrast, the kidney glutathione content increased within 10 min up to 150% upon injection of free glutathione. The findings are consistent with a rapid hydrolysis of extracellular free glutathione followed by an interorgan turnover utilizing the constituent amino acids for resynthesis in the liver. Pretreatment of the animals with the glutathione synthesis inhibitor buthionine sulfoximine essentially abolished the hepatic glutathione increase upon treatment with GSH-liposomes or with the free compound. The finding that only liposomally entrapped glutathione protects mice against liver necrosis induced by highly dosed paracetamol is discussed with respect to differential uptake and distribution of GSH-liposomes in the liver.

Drug-induced lipid peroxidation in mice—I Modulation by monooxegenase activity, glutathione and selenium status

Feeding male mice for 2 days with sucrose leads to a decrease of total liver glutathione by more than 50 per cent when compared to controls. Such animals were intoxicated with 300 mg/kg paracetamol and upon administration of inducers of the drug-metabolizing system, in vivo and vitro lipid peroxidation in these animals was largely increased as well as the susceptibility to the drug. Pretreatment of the mice with methylcholanthrene led to a 28-fold, with benzo(α)pyrene to a 22-fold, and with phenobarbital to a tenfold increase in ethane exhalation. In vivo administration of various monooxygenase inhibitors showed that all agents effectively inhibit paracetamol-induced lipid peroxidation. It is concluded that phase I metabolism of paracetamol is a prerequisite for the manifestation of drug-induced lipid peroxidation. Selenium deficiency in mice neither affected hepatic levels of glutathione nor its decrease following sucrose feeding, nor glutathione transferase, superoxide dismutase, catalase and glutathione reductase activity. Selenium-dependent glutathione peroxidase activity of selenium-deficient mice, reactive with H 2O 2 as well as with t-butylhydroperoxide, decreased to 5 per cent of the supplemented controls. A glutathione peroxidase activity, which utilized cumenehydroperoxide as a substrate but insensitive to selenium deficiency, was found. Selenium-deficient diethylmaleate-pretreated animals were much more susceptible to paracetamol-induced lipid peroxidation than controls. Supplemented diethylmaleate-pretreated animals showed no signs of lipid peroxidation if treated with 100 mg/kg aminopyrine or ethylmorphine. However, deficient animals exhibited high ethane exhalation rates, drastically increased serum transaminases, loss of hepatic glutathione and mortality upon administration of these drugs. Qualitatively similar results with lower ethane exhalation rates were observed when 125 mg/kg furosemide was administered to diethylmaleate-pretreated selenium-deficient or -adequate mice. Even administration of 200 mg/kg ethoxycoumarin in combination with diethylmaleate lead to significant lipid peroxidation in phenobarbital-induced mice. The results demonstrate that in vivo selenium-dependent glutathione peroxidase plays a predominant role within the glutathione redox couple system. The enzyme protects the liver from peroxidative damage evoked by phase I metabolism of various drug types, as long as sufficient glutathione is available. It is suggested that activated oxygen released from the microsomal monooxygenase is the species responsible for the observed lipid peroxidation accompanied by severe acute liver lesions.