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

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.

Kahweol Inhibits Pro-Inflammatory Cytokines and Chemokines in Tumor Necrosis Factor-α/Interferon-γ-Stimulated Human Keratinocyte HaCaT Cells

“…Studies demonstrate kahweol's therapeutic efficacy in various inflammation models, including carrageenan-induced paw edema [26], carbon tetrachloride-induced hepatotoxicity [27], thioacetamide-induced liver fibrosis [28], and traumatic brain injury [29]. Our recent work has also shown kahweol's effectiveness in alleviating cisplatin-induced nephrotoxicity [30] and acetaminophen-induced hepatotoxicity [31] in mice. However, the impact of kahweol on skin inflammation remains unexplored.…”

The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets

“…Kahweol, derived from coffee, alleviated APAP-induced hepatocyte death, and its cell protection was related to the inhibition of ERS. 108 Moreover, the SPHK1 inhibitor PF543 also effectively relieved ERS by reducing the phosphorylation of eIF2α and activating ATF6, thus remarkably improving AIH. 109 Interestingly, guanabenz, a well-known antihypertensive drug, also showed liver protection in AIH mice, which resulted from the reduction of ERS by inhibiting the proteolysis of ATF6.…”

Roles of Coffee and Its Components in Liver Diseases

“…www.journal-dtt.org Kahweol has been shown to possess antioxidant and anti-inflammatory properties, making it effective in mitigating acetaminophen-induced liver damage in mice. This was achieved by restoring glutathione content, inhibiting endoplasmic reticulum (ER) stress-induced cell death in hepatocytes, stimulating the Nrf2-dependent cellular defense system, and reducing NK-κB-mediated inflammation (Kim et al 2022). The ability of kahweol to increase Nrf2 expression was attributed to its reduction of Keap1 protein expression, which occurred independently of p62-dependent autophagy degradation (Seo et al 2020).…”