Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

Gum, Sang Il; Cho, Min Kyung

doi:10.5487/tr.2013.29.3.165

Cited by 95 publications

(63 citation statements)

References 52 publications

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“…NRF2 plays a critical role in the multiple steps related to the alleviation of APAP toxicity and thus is identified as a protective target resistant to liver injury (Gum and Cho, 2013). Furthermore, liver repair is a critical determinant of final outcome of toxicant-induced injury (Diehl and Chute, 2013).…”

Section: Introductionmentioning

confidence: 99%

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

et al. 2014

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Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury.

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Section: Introductionmentioning

confidence: 99%

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

et al. 2014

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“…Because NAPQI covalent binding and APAP protein adducts have already been formed before 4 hours after APAP exposure, GSH replenishment is not a prerequisite event for NRF2 regulates the expression of a battery of cytoprotective genes encoding intracellular detoxifying enzymes and antioxidant proteins that are responsible for GSH synthesis, antioxidant defense, conjugation, transport, and excretion of the metabolites through ARE (Chan et al, 2001). NRF2 plays a critical role in the multiple steps related to alleviation of APAP toxicity and is identified as a protective target for resistance to liver injury (Gum and Cho, 2013). WZ reversed the decreased protein expression of NRF2 target genes including Gclm, Gclc, Nqo1, and Ho-1 by APAP and promoted the recovery of these proteins compared with saline or NAC treatment during APAP-induced liver injury.…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2014

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Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.

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“…Activated Nrf-2 by dissociation from Kelch-like epichlorohydrin-associated protein 1 (Keap1), translocates to the nucleus and binds to the antioxidant response element (ARE) in the promoter region and transcribes a large battery of antioxidant genes (Gum & Cho, 2013;Lee & Pan, 2013). Extensive study reports have demonstrated the fact that Nrf-2 mediated gene regulation is effectually involved in hepatoprotective activity against acetaminophen.…”

Section: Fig 4 -Dose Dependent Effect Of Moringa Oleifera (Mo) Leavementioning

confidence: 99%

The molecular mechanism underlying the hepatoprotective potential of Moringa oleifera leaves extract against acetaminophen induced hepatotoxicity in mice

Karthivashan

Arulselvan

Tan

et al. 2015

Journal of Functional Foods

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Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

Cited by 95 publications

References 52 publications

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

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

The molecular mechanism underlying the hepatoprotective potential of Moringa oleifera leaves extract against acetaminophen induced hepatotoxicity in mice

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