Pathophysiological consequences of enhanced intracellular superoxide formation in isolated perfused rat liver.
The potential toxicity of enhanced intracellular reactive oxygen formation was investigated in isolated perfused livers of male Fischer rats. The presence of the redox-cycling agent diquat in the perfusate (200 microM) increased the basal efflux of glutathione disulfide (GSSG) into bile (2.65 +/- 0.26 nmol GSH-equivalents/min per g liver wt.) and perfusate (0.55 +/- 0.15 nmol/min per g) approximately 10-fold. Since no evidence was found for degradation of GSSG in the biliary tract of these animals, it could be estimated that diquat induced a constant O2- generation of approximately 1000 nmol/min per g liver wt for 1 h. Thus, reactive oxygen formation under these conditions was 1-2 orders of magnitude higher than under various pathophysiological conditions. Only minor liver injury (release of lactate dehydrogenase activity) was observed. To increase the susceptibility of the liver to the oxidant stress, animals were pretreated in vivo with 200 mg/kg body wt. phorone, which caused a 90% depletion of the hepatic glutathione content, 100 mg/kg ferrous sulfate, a combination of phorone and ferrous sulfate, or 40 mg/kg BCNU, which caused a 60% inhibition of hepatic GSSG reductase. Only the combined treatment of phorone + ferrous sulfate or BCNU caused a significant increase of the diquat-induced liver injury. Our results demonstrated an extremely high resistance of the liver against intracellular reactive oxygen formation (even with impaired detoxification systems) and can serve as reference for the evaluation of potential contributions of reactive oxygen to liver injury in various disease states.
Jaeschke
H
H
Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
Benzick
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D000818:Animals; D001646:Bile / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D004178:Diquat / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D007659:Ketones / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism*
D005296:Ferrous Compounds; D007659:Ketones; D013481:Superoxides; C020748:ferrous sulfate; C018637:phorone; D004178:Diquat; D005980:Glutathione Reductase; D005978:Glutathione; D002330:Carmustine