Combination of tauroursodeoxycholic acid and N‐acetylcysteine exceeds standard treatment for acetaminophen intoxication

Paridaens, Annelies; Raevens, Sarah; Colle, Isabelle; Bogaerts, Eliene; Vandewynckel, Yves-Paul; Verhelst, Xavier; Hoorens, Anne; Grunsven, Leo A. van; Vlierberghe, Hans Van; Geerts, Anja; Devisscher, Lindsey

doi:10.1111/liv.13261

Cited by 24 publications

(26 citation statements)

References 41 publications

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“…In addition to the presence of its nucleophilic thiol, which could directly target NAPQI-protein adducts, NAC is a precursor of glutathione, stimulating its synthesis by providing the rate-limiting cysteine precursor, and therefore it is conceivable that the protective effect of NAC in VPAþAPAP hepatotoxicity may imply a dual mechanism involving the prevention of NAQPIprotein adduct formation and glutathione replenishment, thereby abolishing the onset of ER stress, consistent with recent findings in fasted mice treated with APAP. 50 The relevance of the ER stress in the hepatotoxicity caused by VPAþAPAP in nonfasted mice is further demonstrated by the time-dependent sequence of events, in which the onset of ER stress by VPAþAPAP preceded liver injury, and by the ability of the chemical chaperone TUDCA to abolish the induction of ER stress markers and protect against VPAþAPAP-mediated liver injury. Interestingly, both NAC and TUDCA prevented the upregulation of STARD1 by VPAþAPAP, consistent with the causal role of ER stress in inducing STARD1 overexpression, underlying a previously unrecognized ER stress-STARD1 axis in APAP hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

Torres¹,

Baulies²,

Insausti-Urkia³

et al. 2019

Gastroenterology

103

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

Torres¹,

Baulies²,

Insausti-Urkia³

et al. 2019

Gastroenterology

103

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“…APAP overdose-induced liver injury is probably one of the most common causes of drug-induced acute liver failure 30 without effective medication. N-acetylcysteine (NAC) currently is the only drug approved for treatment of APAP overdose-induced liver injury via suppressing ROS at a relatively early stage 31 . IL-22 has been demonstrated to alleviate APAP-induced liver injury; however, the underlying mechanisms remain incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury

Lai

et al. 2018

Theranostics

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Acute or acute-on-chronic liver failure is a leading cause of death in liver diseases without effective treatment. Interleukin-22 (IL-22) is currently in clinical trials for the treatment of severe alcoholic hepatitis, but the underlying mechanisms remain to be explored. Autophagy plays a critical role in alleviating liver injury. The aim of the current study is to explore the role of autophagy in IL-22-mediated hepato-protective effect against acetaminophen (APAP)-induced liver injury.Methods: A model of acute liver injury induced by APAP was used in vivo. IL-22 was administrated to the APAP-treated mice. Hepatocytes were pre-incubated with IL-22, followed by exposure to APAP for in vitro analyses.Results: IL-22 administration significantly reduced serum ALT and AST, hepatic reactive oxygen species, and liver necrosis in APAP-challenged mice. APAP treatment increased hepatic autophagosomes, which was further intensified by IL-22 co-treatment. Hepatic LC3-II was moderately upregulated after APAP administration without obvious alteration of phosphorylation of AMP-activated kinase (p-AMPK). IL-22 pretreatment significantly upregulated hepatic LC3-II and p-AMPK in APAP-treated mice. IL-22 also alleviated APAP-induced cytotoxicity and upregulated LC3-II and p-AMPK expression in cultured hepatocytes treated with APAP in vitro. When p-AMPK was blocked with compound C (an AMPK inhibitor), IL-22-mediated LC3-II conversion and protection against APAP-induced cytotoxicity was weakened.Conclusions: Enhanced AMPK-dependent autophagy contributes to protective effects of IL-22 against APAP-induced liver injury.

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“…NAC seems to detoxify NAPQI toxicity through glutathione supplementation and an anti-oxidative action during APAP hepatotoxicity [ 33 , 34 , 35 ]. Wang et al [22] demonstrated that EtPy has a preventive action on dopamine-induced cell death in PC12 cells, which may be because of the anti-apoptosis action of EtPy.…”

Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

Nagatome

Kondo

Kadowaki

et al. 2018

Heliyon

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Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.

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Combination of tauroursodeoxycholic acid and N‐acetylcysteine exceeds standard treatment for acetaminophen intoxication

Abstract: These findings indicate that a combination strategy of N-acetylcysteine and tauroursodeoxycholic acid surpasses the standard of care in acetaminophen-induced liver injury in mice and might represent an attractive therapeutic opportunity for acetaminophen-intoxicated patients.

Cited by 24 publications

References 41 publications

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury

Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

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