Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of &#945;-Lipoamide Dehydrogenase.

Alexei Kudin,Meir Bialer,Hafiz Mawasi,Arik Eisenkraft,Wolfram Kunz,Christian Elger

doi:10.3390/ijms18091912

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.

Highlights

Valproic acid (VPA; Figure 1) is a widely used classical antiepileptic drug with a high responder rate especially in patients with genetic generalized epilepsies (GGE, former nomenclature—idiopathic generalized epilepsies)
The same preincubation procedure resulted in almost no inhibition of comparable concentration range of VPA (Figure 2A, red diamonds)
The liver toxicity of VPA is one of the most relevant adverse side effects of this broad-spectrum antiepileptic drug. It has been noticed from clinical observations that the liver toxicity of VPA is extremely problematic in Alpers-Hüttenlocher syndrome—a mitochondrial form of epilepsy due to mutations in the mitochondrial DNA polymerase γ affecting brain and liver [1,2,28,29]

Summary

Introduction

Valproic acid (VPA; Figure 1) is a widely used classical antiepileptic drug with a high responder rate especially in patients with genetic generalized epilepsies (GGE, former nomenclature—idiopathic generalized epilepsies). One well known side effect of VPA is its pronounced liver toxicity, which is relevant in genetic epilepsies affecting the brain and the liver. One typical example of an epileptic disorder when the liver toxicity of VPA is extremely relevant is Alpers-Hüttenlocher syndrome caused by mutation in mitochondrial DNA-polymerase γ [1,2]. The detailed reason for VPA’s strong liver toxicity is not very well established, but a strong inhibition of pyruvate oxidation of liver mitochondria by VPA has been noted [3,4]. 2017, 18, 1912; doi:10.3390/ijms18091912 www.mdpi.com/journal/ijms (2R,3S)-VCD and (2S,3S)-VCD, did not show any significant teratogenic effects in SWV/Finn mice—an inbred mouse strain that is highly susceptible to VPA-induced teratogenicity [22,23] Sci. 2017, 18, 1912; doi:10.3390/ijms18091912 www.mdpi.com/journal/ijms (2R,3S)-VCD and (2S,3S)-VCD, did not show any significant teratogenic effects in SWV/Finn mice—an inbred mouse strain that is highly susceptible to VPA-induced teratogenicity [22,23]

Methods

Results

Conclusion