Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice

Botta, Dianne; Shi, Shengli; White, Collin C.; Dabrowski, Michael J.; Keener, Cassie L.; Srinouanprachanh, Sengkeo; Farin, Federico M.; Ware, Carol B.; Ladiges, Warren; Pierce, Robert H.; Fausto, Nelson; Kavanagh, Terrance J.

doi:10.1074/jbc.m605143200

Cited by 54 publications

(50 citation statements)

References 52 publications

(64 reference statements)

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“…The free radicals attack the cell membrane, thus leading to destabilization and disintegration of the cell membrane as a result of lipid peroxidation (Shakun and Vysotski, 1982). In the present study,we observed a marked elevation of hepatic TBARS content following paracetamol administration was in consistence with the other reports in paracetamol-intoxicated rats (James et al, 2003;Botta et al, 2006;Sener et al, 2006). Constituents of P.O.…”

Section: Discussionsupporting

confidence: 93%

Evaluation of in vivo Antioxidant and Hepatoprotective Activity of Portulaca oleracea L. against Paracetamol-Induced Liver Toxicity in Male Rats

Ahmida¹

2010

American Journal of Pharmacology and Toxicology

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Problem statement: Oxidative stress plays a major role in paracetamol induced hepatotoxicity. Portulaca oleracea (P.O.) has been shown to exhibit antioxidant properties. The present study aimed to investigate the effect of P.O. on the oxidative stress in Paracetamol-induced hepatic toxicity in male rats. Approach: Forty male rats were divided into four groups. Group I served as control; Group II Received isotonic saline for 20 days and then simultaneously administered with paracetamol 750 mg kg −1 body wt. every 72 h for 10 days; Group III received freshly prepared P.O. for 30 days; Group IV received freshly prepared P.O. for 20 days and then simultaneously administered with paracetamol 750 mg kg −1 body wt. every 72 h for 10 days. All animals were sacrificed cervical decapitation 24 h after the last application and the blood was collected for the determination of serum marker of lipid peroxidation, antioxidant and histology of the liver was performed. Results: Paracetamol treatment resulted in an increase in the hepatic TBARS content and depletion in total antioxidant capacity, reduced glutathione content, catalase and superoxide dismutase activities. Administration of P.O. with paracetamol significantly ameliorated the indices of hepatotoxicity induced by paracetamol. In addition, P.O. alleviated paracetamol induced oxidative changes in liver. Conclusion: The present study demonstrated that P.O. inhibits paracetamol-induced hepatotoxicity and might serve as a protective agent with paracetamol to limit its free radical induced liver injury.

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Section: Discussionsupporting

confidence: 93%

Evaluation of in vivo Antioxidant and Hepatoprotective Activity of Portulaca oleracea L. against Paracetamol-Induced Liver Toxicity in Male Rats

Ahmida¹

2010

American Journal of Pharmacology and Toxicology

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“…Although we did not observe higher basal GSH levels, which is probably attributable to GSH negative feedback regulation of GCLc activity (Franklin et al, 2009), it is possible that increased GCLc expression enhances GSH synthesis in MLK3-KO mice, which might account for the decreased APAP-induced liver injury in Mlk3(Ϫ/Ϫ) mice. It was demonstrated that overexpression of GCLc does not affect basal GSH levels but enhances GSH resynthesis after APAP-induced GSH depletion, thereby attenuating drug-induced liver injury (Botta et al, 2006). GCLc levels are regulated transcriptionally, post-translationally, and through degradation, and additional studies will be required to address the mechanisms through which MLK3 modulates GCLc levels.…”

Section: Mlk3 In Apap-induced Liver Injurymentioning

confidence: 99%

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

2012

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c-Jun NH 2 -terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3␤ activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wildtype mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.

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“…1, 2, 5, and 6) also suggested that hepatic GSH levels may be increased through FXR-dependent pathways. Gclm functions as a modifier subunit of the glutamate cysteine ligase, the rate-limiting enzyme in GSH biosynthesis (25), and an increase in Gclm was sufficient to increase hepatic GSH biosynthesis (25,26). Interestingly, it has been proposed that APAP-dependent hepatotoxicity is due, at least in part, to depletion of hepatic GSH levels (27)(28)(29).…”

Section: Fxr Provides Protection From Apap-induced Hepatotoxicitymentioning

confidence: 99%

“…Lee et al when compared with wild-type mice (26). The importance of individual FXR-target genes, or combinations of these genes, in providing hepatoprotection from APAP is beyond the scope of the current investigation because it would require studies on multiple knockout mice.…”

mentioning

confidence: 97%

Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

Lee¹,

Vallim

Chong

et al. 2010

Molecular Endocrinology

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The nuclear receptor, farnesoid X receptor (FXR, NR1H4), is known to regulate cholesterol, bile acid, lipoprotein, and glucose metabolism. In the current study, we provide evidence to support a role for FXR in hepatoprotection from acetaminophen (APAP)-induced toxicity. Pharmacological activation of FXR induces the expression of several genes involved in phase II and phase III xenobiotic metabolism in wild-type, but not Fxr(-/-) mice. We used chromatin immunoprecipitation-based genome-wide response element analyses coupled with luciferase reporter assays to identify functional FXR response elements within promoters, introns, or intragenic regions of these genes. Consistent with the observed transcriptional changes, FXR gene dosage is positively correlated with the degree of protection from APAP-induced hepatotoxicity in vivo. Further, we demonstrate that pretreatment of wild-type mice with an FXR-specific agonist provides significant protection from APAP-induced hepatotoxicity. Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP.

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Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice

Cited by 54 publications

References 52 publications

Evaluation of <i>in vivo</i> Antioxidant and Hepatoprotective Activity of <i>Portulaca oleracea</i> L. against Paracetamol-Induced Liver Toxicity in Male Rats

Evaluation of <i>in vivo</i> Antioxidant and Hepatoprotective Activity of <i>Portulaca oleracea</i> L. against Paracetamol-Induced Liver Toxicity in Male Rats

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

Activation of the Farnesoid X Receptor Provides Protection against Acetaminophen-Induced Hepatic Toxicity

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