Therapeutic Doses of Valproate (VAL) Affect Liver Glucose, Fat, Amino Acid, Adenylate, Coenzyme-A (CoA) and Carnitine (CARN) Metabolism in Infant Mice
| Autor: | J H Thurston, J A Schiro, J E Carroll, R E Hauhart |
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| Rok vydání: | 1984 |
| Předmět: | |
| Zdroj: | Pediatric Research. 18:301A-301A |
| ISSN: | 1530-0447 0031-3998 |
| DOI: | 10.1203/00006450-198404001-01247 |
| Popis: | We have reported that chronic VAL administration reduced ketonemia in suckling mice and fasting epileptic children. This study shows that acute VAL has a similar effect. Thirty min after s.c. injection of 4-d-old mice (N=8) with 60 mg/kg of VAL, plasma β-hydroxybutyrate (β-OHB) levels fell 79% (0.197 ± 0.011 mM (mean ± SE) vs 0.952 ± 0.023 in controls), and plasma glucose, 33% (3.95 ± 0.33 mM vs 5.89 ± 0.18). In liver, free CoA levels dropped 67% (22.8 ± 2.5 μmol/kg vs 69.3 ± 4.4), and acetyl-CoA, 73% (7.6 ± 0.7 μmol/kg vs 28.3 ± 2.4) . Liver free CARN decreased 47% (74.5 ± 9.2 μmol/kg vs 140 ± 14). Liver metabolism was inhibited at CoA-requiring steps; pyruvate and α-ketoglutarate levels increased 50%. Citrate and malate levels fell 50%. While liver alanine doubled, levels of aspartate, glutamate and glutamine decreased 40% to 50%. AMP levels fell 34%, but ATP and ADP were unchanged. P values for above differences < 0.001. Since CoA and CARN are essential cofactors in fatty acid oxidation and acetyl-CoA levels control ketogenesis, it is not surprising that VAL reduced plasma β-OHB levels. Glucose and amino acids may be reduced due to their use as metabolic fuels. Gluconeogenesis may also have been inhibited (pyruvate carboxylase is acetyl-CoA dependent). Decreases in aspartate and glutamine support possible decreased AMP synthesis. Findings appear relevant to the hepatotoxicity of VAL in some children and suggest stratagems for prevention and/or treatment. |
| Databáze: | OpenAIRE |
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