Thymoquinone prevents valproic acid-induced hepatotoxicity via modulation of cytochrome P450, PPARs, and apoptotic pathways

Thymoquinone (TQ) is the main bioactive component of Nigella sativa L. and has anti-oxidant, anti-hepatotoxic, anti-cancer, anti-hypertensive, hypoglycemic, anti-inflammatory, and lipid-lowering properties. In this study, we investigated the protective properties of TQ on the cytochrome P450 enzyme system, peroxisome proliferator-activated receptors, and gene expressions involved in apoptosis, which are disrupted by valproic acid (VPA). 

The rats were put into control, VPA, and VPA+TQ groups. The weight of the body and liver were recorded. Liver tissue samples were evaluated for gene expressions (Bcl-2, p53, CYP2B1, CYP2B2, PPARα, and PPARγ), histopatology, and immunohistochemistry (CAS-3 and NOX-4). Additionally, serum was used to measure liver function parameters (ALT, AST, LDH, LDL, and HDL). 

The VPA+TQ group had significantly lower expression of p53 (P<0.05), CYP2B1 (P<0.05), CYP2B2 (P<0.05), PPARα (P<0.05), and PPARγ (P<0.05) genes compared to the VPA groups, while Bcl-2 (P<0.05) gene expression increased. TQ decreased CAS-3 and NOX-4 levels. Also, TQ reduced ALT (P<0.05), AST (P<0.05), LDL (P<0.01), total bilirubin (P<0.05), and LDH (P<0.05) enzyme activity while increasing HDL (P<0.0001). TQ treatment improved fresh liver weight considerably (P<0.0001). 

TQ substantially protects liver tissue by modifying gene expression, lowering oxidative stress, and increasing liver function. It significantly counteracts VPA’s toxic effects, demonstrating its promise as a hepatoprotective agent in avoiding liver damage.