Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation

Acetaminophen (APAP) can cause acute liver failure, but treatment options are still limited. Kahweol is the main diterpene compound of coffee and possesses antioxidant and anti-inflammatory properties. Emerging evidence suggests that this natural diterpene exerts favorable effects on several inflammatory diseases. However, the action of kahweol on APAP toxicity has not been addressed. The purpose of this study was to explore whether kahweol has a protective activity against APAP-induced hepatotoxicity and to investigate the mechanism. Administration of kahweol reduced serum levels of liver injury indicators and ameliorated histological abnormalities in APAP-treated mice. Kahweol inhibited lipid peroxidation and nucleic acid oxidation with restoration of glutathione content and stimulation of nuclear factor erythroid-2-related factor 2-dependent cellular defense system. Hepatocyte death was also decreased by kahweol, which was associated with inhibition of endoplasmic reticulum (ER) stress. Moreover, kahweol reduced hepatic levels of inflammatory mediators, inhibited nuclear factor-κB activation, and attenuated infiltration of neutrophils and macrophages. These findings suggest that kahweol has a protective activity against APAP-induced liver injury and this effect is related to the suppression of oxidative stress, hepatocyte death, ER stress, and inflammation.