4-Methyl-5-Acetylthiazole (Q11), a novel CYP2E1 inhibitor, has a protective effect on the hepatotoxicity induced by acetaminophen

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, primarily due to CYP2E1-mediated generation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). While N-acetylcysteine remains the standard care, its narrow therapeutic window underscores the need for alternative treatment strategies. In this study, we investigated the effects of Q11, a novel CYP2E1 inhibitor, against APAP-induced hepatotoxicity. Molecular docking and enzyme kinetics demonstrated that Q11 coordinates directly to the heme iron of CYP2E1 (bond distance 2.2 Å) and functions as a mixed-type inhibitor with a Ki of 6.0 μM in mouse liver microsomes. Our in vivo results showed that co-treatment with Q11 increased the median lethal dose (LD₅₀) of APAP by 2.4-fold. Moreover, when administered at 60 mg/kg at 3 h post-overdose, Q11 significantly improved the survival rate from 20% to 70% (P < 0.05). Mechanistically, Q11 reduced NAPQI production by 77% (P < 0.001) and inhibited the JNK signaling pathway, thereby restoring APAP-induced mitochondrial dysfunction. These findings suggest that CYP2E1 inhibition represents a promising therapeutic strategy for APAP-induced hepatotoxicity and position Q11 as a compelling candidate for further development.

Acetaminophen hepatotoxicity; CYP2E1 inhibitor; Drug-induced liver injury; Mitochondrial dysfunction; Pharmacokinetics.