Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase.

ABSTRACT: The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibi

SUBMITTER: Kudin AP 

PROVIDER: S-EPMC5618561 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature