An Indole Derivative Protects Against Acetaminophen-Induced Liver Injury by Directly Binding to N-Acetyl-p-Benzoquinone Imine in Mice

Abstract

Aims: Acetaminophen (APAP)-induced liver injury is mainly due to the excessive formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) through the formation of a reactive intermediate, N-acetyl-pbenzoquinone imine (NAPQI), in both humans and rodents. Here, we show that the indole-derived synthetic compound has a protective effect against APAP-induced liver injury in C57Bl/6 mice model. Results: NecroX-7 decreased tert-butylhydroperoxide (t-BHP)-and APAP-induced cell death and ROS/RNS formation in HepG2 human hepatocarcinoma and primary mouse hepatocytes. In mice, NecroX-7 decreased APAP-induced phosphorylation of c-Jun N-terminal kinase ( JNK) and 3-nitrotyrosine (3-NT) formation, and also protected mice from APAP-induced liver injury and lethality by binding directly to NAPQI. The binding of NecroX-7 to NAPQI did not require any of cofactors or proteins. NecroX-7 could only scavenge NAPQI when hepatocellular GSH levels were very low. Innovation: NecroX-7 is an indole-derived potent antioxidant molecule, which can be bound to some types of radicals and especially NAPQI. It is well known that the NAPQI is a major intermediate of APAP, which causes necrosis of hepatocytes in rodents and humans. Thus, blocking NAPQI formation or eliminating NAPQI are novel strategies for the treatment or prevention of APAP-induced liver injury instead of GSH replenishment. Conclusion: Our data suggest that the indole-derivative, NecroX-7, directly binds to NAPQI when hepatic GSH levels are very low and the NAPQI-NecroX-7 complex is secreted to the blood from the liver. NecroX-7 shows more preventive and similar therapeutic effects against APAP-induced liver injury when compared to the effect of N-acetylcysteine in C57Bl/6 mice.

Therapeutic Efficacy of Wuzhi Tablet (Schisandra sphenanthera Extract) on Acetaminophen-Induced Hepatotoxicity through a Mechanism Distinct from N-Acetylcysteine

“…These findings demonstrated that WZ successfully rescued mice from APAP hepatotoxicity and might provide clinically useful means to treat liver injury associated with APAP. NAC had no therapeutic effect on APAP hepatic toxicity when administrated 4 hours after APAP challenge, which was consistent with previous studies (James et al, 2003;Park et al, 2013). Several studies have demonstrated that NAC prevented APAP toxicity when administered before or early (such as 1 or 2 hours) after APAP (Salminen et al, 1998;James et al, 2003).…”

SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions

“…Numerous studies have revealed a role for mitochondrial ROS in the activation of inflammatory signaling pathways to stimulate the production of proinflammatory cytokines, such as TNF, IL6, and IL1B [4,24,25]. Thus we pretreated BMDMs with the mitochondrial-targeted antioxidant MitoTEMPO [26] or NecroX [27] during infection with Mtb or BCG. As shown in Figure 3(g), treatment of BMDMs with MitoTEMPO or NecroX significantly inhibited the Mtbinduced generation of proinflammatory cytokines, including TNF, IL6, IL1B, and CXCL5, in sirt3 −/and Sirt3 +/+ BMDMs in a dose-dependent manner.…”

The Free Radical Scavenger NecroX-7 Attenuates Acute Graft-versus-Host Disease via Reciprocal Regulation of Th1/Regulatory T Cells and Inhibition of HMGB1 Release

“…Recently, one member of this group of compounds, NecroX-7, was shown to inhibit formation of mitochondria-specific ROS/reactive nitrogen species in H9C2 cells and hepatocytes after induction by tert-butyl hydroperoxide or doxorubicin (24,25). NecroX-7 has also been used as an antidote to acetaminophen toxicity (26) and exerts a protective effect by preventing the release of HMGB1 in ischemia/reperfusion injury (27). The ability of NecroX-7 to protect cells and cellular components against oxidative stress and HMGB1 provided a rationale for its use in preventing GVHD induction in the setting of allogeneic HSCT.…”