Predictive biomarkers for valproic acid-induced hepatotoxicity in Chinese patients with epilepsy: the role of metabolites and genetic polymorphisms.

Valproic acid (VPA) is a widely used antiepileptic drug, but its hepatotoxicity limits usage. This study explored biomarkers and genetic factors associated with VPA-induced liver injury in 200 Chinese epileptic patients on VPA monotherapy. We analyzed VPA and its metabolites (4-ene-VPA, 3-OH-VPA, 4-OH-VPA, 2-PGA), liver function, and 22 gene polymorphisms. Patients with abnormal liver function (ANLFT) had significantly higher 4-ene-VPA levels than those with normal liver function (NLFT). The GG genotype of CPT1A rs2228502 was associated with elevated 4-ene-VPA levels. SNPs in ACOT1, PPARα, FFAR2, NQO1, and NRF2 showed significant differences between groups. Logistic regression identified NRF2 rs59288687 and NQO1 rs10517 as protective factors against hepatotoxicity. In conclusion, elevated 4-ene-VPA and genetic variants, including CPT1A rs2228502, NRF2 rs59288687, and NQO1 rs10517, influence hepatotoxicity risk, providing insights for individualized treatment strategies.