Abstract
Valproic acid (VPA) is a widely used antiepileptic drug and also prescribed to treat migraine, chronic headache and bipolar disorder. Although it is usually well tolerated, a severe hepatotoxic reaction has been repeatedly reported after VPA administration. A profound toxic reaction on administration of VPA has been observed in several patients carrying POLG mutations, and heterozygous genetic variation in POLG has been strongly associated with VPA-induced liver toxicity.Here we studied the effect of VPA in fibroblasts of five patients carrying pathogenic mutations in the POLG gene. VPA administration caused a significant increase in the expression of POLG and several regulators of mitochondrial biogenesis. It was further supported by elevated mtDNA copy numbers. The effect of VPA on mitochondrial biogenesis was observed in both control and patient cell lines, but the capacity of mutant POLG to increase the expression of mitochondrial genes and to increase mtDNA copy numbers was less effective. No evidence of substantive differences in DNA methylation across the genome was observed between POLG mutated patients and controls. Given the marked perturbation of gene expression observed in the cell lines studied, we conclude that altered DNA methylation is unlikely to make a major contribution to POLG-mediated VPA toxicity. Our data provide experimental evidence that VPA triggers increased mitochondrial biogenesis by altering the expression of several mitochondrial genes; however, the capacity of POLG-deficient liver cells to address the increased metabolic rate caused by VPA administration is significantly impaired.
Highlights
Valproic acid (2-propyl-pentanoic acid, VPA) is a widely prescribed antiepileptic drug used in several different types of epilepsy, and in other neurological conditions such as bipolar disease, migraine prophylaxis, alcohol and other sedative-hypnotic withdrawal syndromes and occasionally for chronic pain [1,2,3]
1/3 of Alpers–Huttenlocher syndrome (AHS) patients developed liver failure within 3 months of exposure to VPA [9,10]. This raises the possibility that genetic variation in polymerase γ (POLG) may predispose individuals to VPAinduced liver failure who may not have a recognizable phenotype like AHS [11]
In order to define the mechanism of VPA toxicity in POLGrelated disease, we performed further in vitro studies including a search for an epigenetic mechanism, given the known role of VPA as a histone deacetylase (HDAC) inhibitor
Summary
Valproic acid (2-propyl-pentanoic acid, VPA) is a widely prescribed antiepileptic drug used in several different types of epilepsy, and in other neurological conditions such as bipolar disease, migraine prophylaxis, alcohol and other sedative-hypnotic withdrawal syndromes and occasionally for chronic pain [1,2,3]. VPA is usually well tolerated, severe hepatotoxic reaction including Reye-like liver failure and VPAinduced hyperammonemic encephalopathy have been reported over the last decades [2]. K.S. Sitarz et al / Molecular Genetics and Metabolism 112 (2014) 57–63 characterized by developmental delay and intractable epilepsy and liver disease [6,7]. 1/3 of AHS patients developed liver failure within 3 months of exposure to VPA [9,10]. This raises the possibility that genetic variation in POLG may predispose individuals to VPAinduced liver failure who may not have a recognizable phenotype like AHS [11]. In order to define the mechanism of VPA toxicity in POLGrelated disease, we performed further in vitro studies including a search for an epigenetic mechanism, given the known role of VPA as a histone deacetylase (HDAC) inhibitor
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