Hepatic mitochondrial oxidative metabolism and lipid peroxidation in experimental hexachlorobenzene-induced porphyria with dietary carbonyl iron overload.
Both human porphyria cutanea tarda and experimental hexachlorobenzene-induced porphyria are associated with hepatic injury and are potentiated by excess hepatic iron. The mechanisms whereby cellular injury occurs and the synergistic role of iron overload are unknown. In the present experiments, we studied hepatic mitochondrial function and lipid peroxidation in rats with hexachlorobenzene-induced porphyria in which iron loading was achieved by dietary carbonyl iron supplementation. Female rats were treated for 8 weeks, receiving a chow diet supplemented with hexachlorobenzene (0.2%, w/w), carbonyl iron (1.0%, w/w) or hexachlorobenzene + iron. Hepatic total porphyrins were increased 100-fold in rats receiving hexachlorobenzene (hexachlorobenzene alone and hexachlorobenzene + Fe), and total hepatic iron was increased approximately 10-fold in rats receiving iron supplementation (Fe alone and hexachlorobenzene + Fe). There was a significant increase in mitochondrial lipid peroxidation in rats treated with hexachlorobenzene alone and hexachlorobenzene + Fe. A significant reduction in mitochondrial respiratory control ratios and in oxidative phosphorylation (ADP/O ratios) using glutamate and succinate as substrates was demonstrated when rats were treated with hexachlorobenzene + iron. The reductions in respiratory control ratios were due to a combination of an inhibitory defect in electron transport as evidenced by an irreversible decrease in State 3 respiration and an uncoupling effect as evidenced by an increase in State 4 respiration. These findings suggest that lipid peroxidation and mitochondrial dysfunction may contribute to the hepatotoxicity seen in hexachlorobenzene-induced porphyria.
Feldman
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Department of Medicine, Case Western Reserve University School of Medicine, Cleveland Metropolitan General Hospital, Ohio 44109.
Bacon
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BR
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000633:toxicity*; D004032:Diet; D005260:Female; D006581:Hexachlorobenzene / Q000633:toxicity*; D007501:Iron / Q000633:toxicity*; D054354:Iron Carbonyl Compounds; D015227:Lipid Peroxidation; D008930:Mitochondria, Liver / Q000378:metabolism*; D009942:Organometallic Compounds / Q000633:toxicity*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D011164:Porphyrias / Q000139:chemically induced*; D051381:Rats; D011919:Rats, Inbred Strains
D002722:Chlorobenzenes; D009942:Organometallic Compounds; D054354:Iron Carbonyl Compounds; D006581:Hexachlorobenzene; D007501:Iron