Epinephrine-mediated sensitization of thioredoxin 1 enhances chlorpromazine protection against acute hepatotoxicity.

Acute liver injury (ALI) is characterised by rapid hepatic necrosis and compromised liver functions. Drug-induced ALI, in particular, is associated with glutathione depletion and overproduction of reactive oxygen species (ROS). These alterations highlight the contribution of the thioredoxin system (Trx/TrxR/NADPH) in preserving hepatic redox homeostasis. Previously, we demonstrated that thioredoxin-1 (Trx1) overexpression exerts protective effects against ischemic heart and peripheral vascular disease. Also, the neuroprotective role of thioredoxin reductase (TrxR1) has been reported in Parkinson's Disease. However, it remains unclear whether epinephrine (EP)-mediated boosting of the thioredoxin system, together with chlorpromazine (CPZ), provides sufficient protection against drug-induced ALI. To investigate this hypothesis, C57BL/6 mice were chronically administered a low dose of EP to enhance the expression of Trx1/TrxR1, followed by ALI induction with N-acetyl-para-aminophenol (APAP) and treatment with a subtoxic dose of CPZ. In parallel, hepatoma cell lines were treated with EP and/or CPZ to monitor the associated subcellular and molecular changes. The results showed that EP enhanced the expression of Trx1, thioredoxin-like protein 1 (TrxL1), and TrxR1 in liver and TrxR1 in hepatoma cell lines. Also, EP attenuated liver injury and enhanced the therapeutic effect of CPZ in ALI mice. A significant improvement in liver biomarkers, resolution of inflammation, attenuated oxidative stress, and restoration of hepatic histological architecture accompanied these observations. Moreover, activation of the thioredoxin system in hepatoma cells was associated with overexpression of β-arrestin1, TrxL1, and cAMP-response element-binding protein (CREB1), mirroring their involvement in Trx-mediated protection. Conclusively, these results addressed the protective role of boosting the cytosolic thioredoxin system in drug-induced ALI.