Metabolic effects of valproate on dog renal cortical tubules.
The effect of valproate (0.01-10 mM), an antiepileptic drug inducing hyperammonemia in humans, was studied in vitro on a suspension of renal cortical tubules (greater than 85% proximal tubules) obtained from six normal dogs. When these tubules were incubated with 1 mM glutamine, the addition of valproate accelerated glutamine uptake, ammoniagenesis, and the production of alanine, lactate, and pyruvate. With 5 mM glutamine, a rise in glutamate accumulation, a much greater synthesis of alanine, an important aspartate production, and a striking accumulation of lactate and pyruvate were observed. With 1 or 5 mM lactate, lactate utilization and gluconeogenesis were markedly reduced with increasing concentrations of valproate. Oxygen consumption was reduced by only 15-20% by 10 mM valproate. The accelerated glutamine utilization resulting from valproate could not be prevented by aminooxyacetate, an inhibitor of transamination. Valproate also reduced various enzymatic activities, a finding that could not explain its metabolic effects. Four sites of action may explain these various metabolic changes: (i) a stimulation of mitochondrial glutamine transport, (ii) an increase in the flux of glutamate to malate, and (iii) a reduction in the net oxidation of pyruvate and (iv) in the flux through pyruvate carboxylase.
Gougoux
A
A
Renal Service, Notre-Dame Hospital, Montréal, Qué., Canada.
Vinay
P
P
D000625:Aminooxyacetic Acid / Q000378:metabolism; D000818:Animals; D004285:Dogs; D005971:Glutamates / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
D005971:Glutamates; D007773:Lactates; D011773:Pyruvates; D005973:Glutamine; D000625:Aminooxyacetic Acid; D014635:Valproic Acid