Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity

Abstract

Valproic acid (VPA), a widely prescribed antiepileptic drug, is known to induce hepatotoxicity. However, the mechanisms underlying this toxicity are not well understood. In this study, we performed a nontargeted metabolomic analysis of children with epilepsy treated with VPA (n = 23). Metabolic pathway analysis showed that the fatty acid pathway, citrate cycle, urea cycle, amino acid metabolism, and bile acid pathway were altered in children with epilepsy exhibiting VPA hepatotoxicity. In particular, the VPA-induced perturbation of bile acid homeostasis has not been observed previously. Based on these findings, we performed a targeted metabolomic analysis to characterize bile acid profiles and further determined the effects of VPA on the synthesis, transport, and regulation of bile acids in mice. The bile acid metabolomic profiles of the livers of mice treated with VPA indicated an increase in most bile acids, especially chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), as well as unconjugated bile acids. The upregulation of genes related to bile acid synthesis (CYP7A1 and CYP8B1) and the downregulation of genes related to conjugation (BAAT and BACS) and regulation (FXR and SHP) were detected in the liver, suggesting that hydrophobic bile acid production was increased and FXR signaling was impaired. Our results suggest that the perturbation of bile acid homeostasis and impaired FXR signaling are involved in VPA-induced hepatotoxicity, providing a novel insight into VPA hepatotoxicity.