Abstract
Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.
Highlights
The liver is vulnerable to multiple factors, including various drugs which result in liver injury or/and Acute Liver Failure (ALF) (Bernal et al, 2015)
To investigate whether Licochalcone A (Lico A) could protect against APAPinduced ALF in mice, the survival rate firstly was observed within 48 h after APAP exposure
Our results indicated that alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum were significantly increased by APAP administration when compared with Control group
Summary
The liver is vulnerable to multiple factors, including various drugs which result in liver injury or/and ALF (Bernal et al, 2015). Acetaminophen (N-acetyl-p-aminophenol) is a valid antipyretic and analgesic drug, whereas taking overdose APAP leads to severe liver injury (Jaeschke, 2015). The APAP-induced hepatotoxicity is associated with overproduction of reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) predominantly via CYP2E1—the classical cytochrome P450 isozyme, which attributes to cause depletion of glutathione (GSH) and formation of ROS triggering oxidative stress to result in mitochondrial dysfunction, hepatocyte necrosis, and even liver injury (McGill and Jaeschke, 2013; Huo et al, 2017). GSH and oxidized glutathione (GSSG) belong to the glutathione pool which is an essential redox buffer in various cells, and their ratios of change are thought to be an indicator of intracellular redox status (Schafer and Buettner, 2001), which plays an important role in the attenuation of APAP-induced ALF (Du et al, 2017). The inhibition of oxidative stress may play an essential role in attenuating APAP-induced ALF. Previous studies have suggested that Nrf2-deficiency mice have the greater severity than the wild-type (WT) mice in APAP-induced liver injury (Enomoto et al, 2001), targeting Nrf activation for effective prevention of hepatotoxicity
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