Abstract
Recently there have been reports of a Reye's-like hepatoencephalopathy with hyperammonemia, fatty infiltration of the liver, hypoglycemia, and progressive obtundation, associated with the use of the anticonvulsant, valproic acid (VPA). We evaluated the effects of VPA on liver metabolism with the consideration of developing a model for studying Reye's syndrome. Rates of K (umol/hr/gm dry weight) by rat hepatocytes incubated with 0.5 mM VPA (optimal serum levels 0.5 mM - 1.0 mM) and ketogenic substrates are presented below:
VPA inhibited U by 75% and G by 60%. With isolated mitochondria, VPA (20uM) inhibited oxidation of palmityl carnitine, but had no effect on pyruvate oxidation, suggesting that VPA inhibits an enzyme(s) of fatty acid oxidation. The inhibition of U and G by VPA may reflect decreased fatty acid oxidation with consequent decreased acetyl CoA and NADH or specific inhibition of other enzymes of these pathways. Inhibition of U and G is also consistent with the clinical picture seen in VPA toxicity. VPA is more likely to be toxic under fasting conditions. This model may be useful for the study of metabolic abnormalities associated with Reyes Syndrome.
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Hale, D., Corkey, B. & Stanley, C. EFFECTS OF VALPROIC ACID (DEPAKENE) ON KETOGENESIS (K), GLUCONEOGENESIS (G), AND UREAGENESIS (U) BY RAT HEPATOCYTES. Pediatr Res 18 (Suppl 4), 294 (1984). https://doi.org/10.1203/00006450-198404001-01207
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DOI: https://doi.org/10.1203/00006450-198404001-01207