The characterization of perfluorosuccinate as an inhibitor of gluconeogenesis in isolated rat hepatocytes.
The effects on metabolism of the fluorinated dicarboxylic acid, perfluorosuccinate, were examined in hepatocytes from fasted rats. Perfluorosuccinate (5 mM) inhibited gluconeogenesis from lactate by 80% and from pyruvate by 40%. Significant inhibition (up to 30%) occurred at a concentration of perfluorosuccinate of 50 microM. Cellular ATP levels were not affected by perfluorosuccinate, nor was the rate of formation of ketone bodies from palmitate, although the ratio [3-hydroxybutyrate]/[acetoacetate] was increased up to 5-fold relative to the control. An increased concentration of cellular L-malate was measured in the presence of perfluorosuccinate but this did not reflect inhibition of malate transport between the mitochondrial and cytoplasmic compartments. In addition, ethanol oxidation by hepatocytes was inhibited 25% by 1 mM perfluorosuccinate. Ureogenesis from ammonia was relatively insensitive to inhibition by perfluorosuccinate. In cytoplasmic extracts of rat liver, the activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase were inhibited 40-50% and 23%, respectively, by 1 mM perfluorosuccinate. The observed metabolic effects of perfluorosuccinate are consistent with inhibition of the activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase within the cytoplasm.
Department of Medical Biochemistry, School of Medicine, Flinders University of South Australia, Bedford Park.
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Gregory
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Berry
D000818:Animals; D000963:Antimetabolites; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors; D000431:Ethanol / Q000378:metabolism; D005466:Fluorocarbons / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008293:Malates / Q000378:metabolism; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013386:Succinates / Q000494:pharmacology* / Q000502:physiology; D019802:Succinic Acid
D000963:Antimetabolites; D005466:Fluorocarbons; D007773:Lactates; D008293:Malates; D011773:Pyruvates; D013386:Succinates; D019344:Lactic Acid; C060763:perfluorosuccinic acid; D000431:Ethanol; C030298:malic acid; D019289:Pyruvic Acid; D019802:Succinic Acid; D001219:Aspartate Aminotransferases; D010729:Phosphoenolpyruvate Carboxykinase (GTP)