Abstract
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.
Highlights
Acute liver failure (ALF) is a clinical condition characterized by the abrupt decline of liver function in patients without underlying liver disease, often accompanied by jaundice, coagulopathy, and hepatic encephalopathy [1]
Serum AST and ALT levels were elevated after APAP treatment (Figures 1(a) and 1(b))
We showed that kahweol protected against APAP-induced acute hepatotoxicity via inhibition of oxidative stress, hepatocyte death, endoplasmic reticulum (ER) stress, and inflammation
Summary
Acute liver failure (ALF) is a clinical condition characterized by the abrupt decline of liver function in patients without underlying liver disease, often accompanied by jaundice, coagulopathy, and hepatic encephalopathy [1]. The causes of ALF include viral hepatitis, drugs, and toxins [1]. APAP is known to be safe when used at recommended doses, its overdose is considered the leading cause of ALF worldwide [2]. While this drug is primarily converted into nontoxic adducts and excreted in the urine, some are converted to form N-acetyl-p-benzoquinone imine (NAPQI) [3]. At recommended doses of APAP, the toxic metabolite can be neutralized via conjugation with endogenous glutathione (GSH). An overdose of APAP induces NAPQI accumulation along with GSH depletion, leading to the development of oxidative stress, hepatocellular death, and liver injury [3]
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