Histidine, carnosine, and ergothioneine attenuate pyrazole/LPS-induced hepatotoxicity through modulation of CYP2E1, Nrf2, and NF-κB signaling in mice.

BACKGROUND/AIM: Cytochrome P450 2E1 (CYP2E1) is key in liver damage from oxidative stress. The pyrazole (Pyr)- and lipopolysaccharide (LPS)- induced mouse model, which combines CYP2E1 induction with endotoxemia, is useful for studying liver protection. This study assessed how imidazole compounds (histidine, carnosine, and ergothioneine) affect Pyr + LPS-induced liver injury and the mechanisms involved.

METHODS

Male C57BL/6J mice received histidine (250 mg/kg, i.p.), carnosine (250 mg/kg, i.p.), histidine + carnosine (250 mg/kg each, i.p.), or ergothioneine (70 mg/kg, oral) for 10 consecutive days. Pyrazole (150 mg/kg, i.p.) was administered on days 8 and 9, followed by LPS (10 mg/kg, i.p.) on day 10. Serum ALT and AST activities, hepatic oxidative stress markers (ROS, TBARS, AOPP), antioxidant parameters (GSH, SOD, GSH-Px, FRAP), CYP2E1 protein levels, nitric oxide metabolites (NOx), and mRNA expressions of Nrf2, HO-1, NF-κB, TNF-α, and IL-6 were determined. Histopathological examination was also performed.

RESULTS

Pyr + LPS administration significantly elevated serum ALT and AST levels, hepatic CYP2E1, oxidative stress markers, and NOx, while reducing antioxidant defenses. NF-κB, TNF-α, IL-6, and HO-1 mRNA expressions were elevated. Pre-treatment with all imidazole compounds significantly attenuated these alterations, reduced CYP2E1 levels, and further upregulated HO-1 expression. The combination of histidine and carnosine also increased Nrf2 mRNA expression. Histopathological findings corroborated the biochemical results.

CONCLUSION

Histidine, carnosine, and ergothioneine protected against Pyr + LPS-induced hepatic injury and reduced oxidative stress. These effects were accompanied by alterations in CYP2E1 protein levels and NF-κB/Nrf2/HO-1-related gene expression; however, further studies are needed to clarify the underlying mechanisms.