Editor’s Highlight: Metformin Protects Against Acetaminophen Hepatotoxicity by Attenuation of Mitochondrial Oxidant Stress and Dysfunction

Abstract

Overdose of acetaminophen (APAP) causes severe liver injury and even acute liver failure in both mice and human. A recent study by Kim et al. (2015, Metformin ameliorates acetaminophen hepatotoxicity via Gadd45β-dependent regulation of JNK signaling in mice. J. Hepatol. 63, 75-82) showed that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. However, its exact protective mechanism has not been well clarified. To investigate this, C57BL/6J mice were treated with 400 mg/kg APAP and 350 mg/kg metformin was given 0.5 h pre- or 2 h post-APAP. Our data showed that pretreatment with metformin protected against APAP hepatotoxicity, as indicated by the over 80% reduction in plasma alanine aminotransferase (ALT) activities and significant decrease in centrilobular necrosis. Metabolic activation of APAP, as indicated by glutathione depletion and APAP-protein adducts formation, was also slightly inhibited. However, 2 h post-treatment with metformin still reduced liver injury by 50%, without inhibition of adduct formation. Interestingly, neither pre- nor post-treatment of metformin inhibited c-jun N-terminal kinase (JNK) activation or its mitochondrial translocation. In contrast, APAP-induced mitochondrial oxidant stress and dysfunction were greatly attenuated in these mice. In addition, mice with 2 h post-treatment with metformin also showed significant inhibition of complex I activity, which may contribute to the decreased mitochondrial oxidant stress. Furthermore, the protection was reproduced in JNK activation-absent HepaRG cells treated with 20 mM APAP followed by 0.5 or 1 mM metformin 6 h later, confirming JNK-independent protection mechanisms. Thus, metformin protects against APAP hepatotoxicity by attenuating the mitochondrial oxidant stress and subsequent mitochondrial dysfunction, and may be a potential therapeutic option for APAP overdose patients.

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

“…In conclusion, our study supports the results of previous studies that show memory loss due to DOX treatment using behavioral tests. Although MET can reduce the cytotoxic effects of several chemotherapy agents (such as nephrotoxicity, hepatotoxicity, and cardiotoxicity [9,31,32]), it failed to reduce neurotoxicity induced by DOX treatment in this study. Therefore, further clinical studies are needed to investigate the protective effects of MET on neurotoxicity in humans.…”

Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity

“…In addition, caspase-3, the main executioner of apoptosis, is not activated after APAP overdose, and pan-caspase inhibitors do not protect against APAP hepatotoxicity (Lawson et al 1999; Adams et al 2001; Gujral et al 2002; Jaeschke et al 2006). Intriguingly, some features that were previously considered specific for apoptosis are still noticed during APAP toxicity, such as mitochondrial bax translocation and release of cytochrome C and Smac/DIABLO from mitochondria through bax pores (Adams et al 2001; Knight and Jaeschke 2002; Bajt et al 2008; Du et al 2016b). Although the lower ATP levels in the fasted mice were thought to be responsible for the absence of caspase activation and the subsequent caspase-mediated apoptotic cell death (Antione et al 2009; 2010), no morphological evidence for apoptosis and no protection with caspase inhibitors were found in fed mice despite their higher ATP levels in the liver (Williams et al 2011).…”

Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity

“…Complex I of the mitochondrial electron transport chain is known to be an important source of ROS formation [37] and biguanides such as metformin are known to arrest complex I in the deactivated state and thereby preventing ROS leakage [38]. Consistent with these observations, metformin profoundly protected against APAP hepatotoxicity by inhibiting complex I thereby substantially attenuating the mitochondrial oxidant stress [39]. MCJ (methylation-controlled J protein), an endogenous regulator of complex I, reduces its activity [40].…”

“…The regulation of the MTP has been shown to be influenced by matrix calcium and free radicals, and is also dependent on electron flux through the electron transport chain, especially from complex I [97]. This is relevant in light of the earlier mentioned, beneficial effect of metformin against APAP hepatotoxicity [39], which inhibited complex I activity. The molecular composition of the mitochondrial permeability transition pore (MPTP) has been under intense investigation for decades and the current consensus implicates the proteins Bax and Bak as its components on the outer mitochondrial membrane [98,99], which function along with subunits of the ATP synthase on the inner mitochondrial membrane [94].…”