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Int. J. Mol. Sci. 2017, 18(9), 1912; doi:10.3390/ijms18091912

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

1
Department of Epileptology and Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany
2
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
3
Institute for Research in Military Medicine, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
*
Author to whom correspondence should be addressed.
Received: 28 July 2017 / Revised: 1 September 2017 / Accepted: 3 September 2017 / Published: 6 September 2017
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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 inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec-butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec-butylpropylacetamide (SPD) and valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy. View Full-Text
Keywords: valproic acid; analogues of valproic acid; liver toxicity; metabolic epilepsy; mitochondrial epilepsy valproic acid; analogues of valproic acid; liver toxicity; metabolic epilepsy; mitochondrial epilepsy
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MDPI and ACS Style

Kudin, A.P.; Mawasi, H.; Eisenkraft, A.; Elger, C.E.; Bialer, M.; Kunz, W.S. Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase. Int. J. Mol. Sci. 2017, 18, 1912.

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