Studies on the inhibition of gluconeogenesis by oxalate.
Oxalate was shown to enter isolated rat hepatocytes and to inhibit gluconeogenesis from lactate, pyruvate, and alanine, but not from glutamine, proline, propionate or dihydroxyacetone. Oxalate apparently acts by inhibiting pyruvate carboxylase (EC 6.4.1.1.). It is known to inhibit the isolated enzyme, and inhibition of gluconeogenesis was much greater in a bicarbonate-deficient medium where pyruvate carboxylase activity limits the overall rate of the pathway. A slight inhibition of gluconeogenesis from asparagine was observed, suggesting that oxalate may also inhibit gluconeogenesis at another site. Chelation of extracellular Ca2+ does not contribute to the inhibition of gluconeogenesis. Compared to oxalate, other Ca2+ chelators have little effect upon gluconeogenesis. Also, oxalate inhibits gluconeogenesis effectively both in low Ca2+ medium and in medium containing 2.6 mM Ca2+. Chelation of intracellular Ca2+ also appears to be of little importance, since oxalate does not block the glycogenolytic effects of epinephrine, vasopressin, and angiotensin which are thought to act via Ca2+ as the second messenger. The inhibition of gluconeogenesis could conceivably contribute to the toxic actions of oxalate and to the hypoglycemic action of dichloroacetate, a compound that is metabolized to oxalate. However, oxalate did not cause hypoglycemia in the suckling rat, a model in vivo system very dependent upon gluconeogenesis for maintenance of normal blood glucose levels. Thus, inhibition of gluconeogenesis is probably of little importance in oxalate toxicity and the hypoglycemic effects of dichloroacetate.
D000809:Angiotensins / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D010070:Oxalates / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D014667:Vasopressins / Q000494:pharmacology
D000809:Angiotensins; D001786:Blood Glucose; D008112:Liver Glycogen; D010070:Oxalates; D014667:Vasopressins; D004533:Egtazic Acid; D004492:Edetic Acid; D003999:Dichloroacetic Acid; D002118:Calcium; D004837:Epinephrine