Effect of As2O3 on gluconeogenesis.
1) The effect of As2O3 and As2O5 on gluconeogenesis from various substrates in the liver and kidney of rats was investigated. 2) A concentration-dependent inhibition by As2O3 was found. The effect was not dependent on the amount of investigated material (hepatocytes or kidney tubules). For either hepatocytes or kidney tubules the extent of inhibition depended strongly on the substrate used. The highest degree of inhibition was observed in incubations with pyruvate. The inhibition of glucose formation was accompanied to a lesser extent by a diminution in O2 consumption and ATP content. The effect was also dependent on the substrate used. Maximum effect was found in incubations with pyruvate. 3) Oleate, 0.5 mmol/l, increased gluconeogenesis from pyruvate. The effect was not abolished by As2O3. 4) A decrease in the content of acetyl-CoA, 3-hydroxybutyrate, and reduced glutathione was found in suspensions of isolated rat kidney tubules or hepatocytes incubated with As2O3. 5) About 10 times higher concentrations of As2O5 were necessary to induce a similar extent of inhibition of gluconeogenesis, decrease in O2 consumption, and in ATP content as compared with As2O3. The extent of the As2O5 effect depended on the concentration of the toxicant and on the substrate used. Gluconeogenesis from pyruvate exhibited the highest sensitivity to As2O5. 6) All findings can be largely explained by inhibition of pyruvate dehydrogenase as the central target for arsenicals. The subsequent depletion of acetyl CoA results in impaired formation of reducing equivalents in the citric acid cycle, decrease in high energy phosphates and, acetyl CoA being a strong positive modulator of pyruvate carboxylase, in gluconeogenesis inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Szinicz
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Institut für Pharmakologie und Toxikologie der Akademie des Sanitäts- und Gesundheitswesens der Bundeswehr-BSW, Ingolstädter, Garching-Hochbrück, Federal Republic of Germany.
Forth
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D000090:Acetoacetates / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D005215:Fasting; D005943:Gluconeogenesis / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006885:Hydroxybutyrates / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D010087:Oxides; D051381:Rats; D011919:Rats, Inbred Strains
D000090:Acetoacetates; D001152:Arsenicals; D006885:Hydroxybutyrates; D010087:Oxides; C042120:arsenic pentoxide; D000105:Acetyl Coenzyme A; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D001151:Arsenic; D000077237:Arsenic Trioxide