It is well known that in some individuals, administration of valproic acid leads to hepatotoxicity. The causes for this are not completely understood, though mutations in POLG are a well known risk factor. In a fibroblast model, Luis et al (JIMD, (2014) 37 353-357) found that Valproyl-CoA inhibited the activities of both GTP- and ATP-specific succinate:CoA ligases to a significant degree. Possibly this leads to impaired energy metabolism due to abnormal Krebs cycle flux. The authors also postulate that inhibition of ATP-specific succinate:CoA ligase might disturb nucleoside diphosphate kinase activity leading to an imbalance of mitochondrial nucleotides and therefore mitochondrial DNA depletion. This theory does provide an explanation as to why POLG mutations are a particular susceptibility factor for valproate toxicity.
Hilary Vernon, MD PhD