An effective assessment of valproate sodium-induced hepatotoxicity with UPLC–MS and 1HNMR-based metabonomics approach

•UPLC–MS and 1HNMR based metabonomic approach were used to assess the hepatotoxicity induced by VPA.•Separation were achieved between VPA induced NLFT and ANLFT patients’ serum metabolite profiles.•Several metabolites in the serum were identified as potential biomarkers.•VPA induced hepatotoxicity disturbed glycolysis, lipid, energy and some amino acids metabolism.

Valproate sodium is one of the most prescribed antiepileptic drugs. However, valproate sodium has various side effects, especially its toxicity on liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods for toxicity evaluation are desired. To evaluate the toxicity of valproate sodium on liver, we performed both UPLC–MS and 1HNMR-based metabonomics analysis of serum samples from 34 epileptic patients (age: 42.0 ± 18.6, 18 male/16 female) after valproate sodium treatment. Compared to conventional markers, the serum metabolic profiles provided clear distinction of the valproate sodium induced normal liver function and abnormal liver function in epileptic patients. Through multivariate statistical analysis, we identified marker metabolites associated with the hepatotoxicity induced by valproate sodium, such as glucose, lactate, acetoacetate, VLDL/LDL, lysophosphatidylcholines, phosphatidylcholines, choline, creatine, amino acids, N-acetyl glycoprotein, pyruvate and uric acid. This metabonomics approach may provide effective way to evaluate the valproate sodium-induced toxicity in a manner that can complement current measures. This approach is expected to find broader application in other drug-induced toxicity assessment.