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      Mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin on intermediary metabolism in the rat.

      The Journal of pharmacology and experimental therapeutics

      Animals, Body Weight, drug effects, Eating, Fatty Acids, metabolism, Injections, Intraperitoneal, Liver, Male, Oxidation-Reduction, Rats, pharmacology, Rats, Inbred Strains, Tetrachlorodibenzodioxin

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          A single 20-microgram/kg dose of TCDD caused, within 3 days, a significant mobilization of depot fat into the plasma compartment resulting in 1.44- to 2.8-fold increase in plasma free-fatty acid concentrations. With respect to the fate of mobilized fatty acids, the same treatment of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused a 32% inhibition (P less than .008) of the rate of hepatic oleate oxidation without significantly affecting the rate of fatty acid esterification. In contrast, hepatic ketogenic rate from oleate and octanoate was stimulated markedly by 85% (P less than .001) and 69% (P less than .001), respectively. These results support the concept that although the beta-oxidation pathway of the fatty acids must be operating normally, their complete oxidation to CO2 via the Tricarboxylic acid (TCA) cycle is impaired. At the same time, TCDD seems to preferentially divert the acetyl CoA generated from the beta-oxidation of fatty acids to the ketogenic pathway. Surprisingly, TCDD treatment inhibited the hepatic ketogenic rate from glycerol by 21% (P less than .001) and its oxidation to CO2 by 31% (P less than .025) without affecting its esterification to triglycerides. These results imply that the other possible major site which is sensitive to TCDD inhibition may be the generation of acetyl CoA from glycerol via the pyruvate dehydrogenase complex.

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