Acetaminophen induces ER dependent signaling in mouse liver

Nagy, Gábor; Kardon, Tamás; Wunderlich, Lívius; Szarka, András; Kiss, András; Schaff, Zsuzsa; Bánhegyi, Gábor; Mandl, József

doi:10.1016/j.abb.2006.11.021

Cited by 94 publications

(72 citation statements)

References 35 publications

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“…In addition the total GSH levels have also been determined to assess the potential influence of ferrostatin-1 on the detoxification status of the cells especially on the conjugation of the highly reactive NAPQI by GSH. As it was also expected on the base of our previous results [17,23] APAP treatment significantly depleted the cellular GSH pool (Table 4.). However it seems that ferrostatin-1 treatment did not have any influence on the cellular GSH level (Table 4.).…”

Section: The Effect Of Ferrostatin-1 On the Expression Of Cyp2e1 And supporting

confidence: 90%

Ferroptosis is Involved in Acetaminophen Induced Cell Death

Lőrincz

Jemnitz

Kardon

et al. 2015

Pathol. Oncol. Res.

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167

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The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes.

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Section: The Effect Of Ferrostatin-1 On the Expression Of Cyp2e1 And supporting

confidence: 90%

Ferroptosis is Involved in Acetaminophen Induced Cell Death

Lőrincz

Jemnitz

Kardon

et al. 2015

Pathol. Oncol. Res.

Self Cite

167

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“…The toxicity of acetaminophen and its mechanisms have been extensively studied for decades because of its complexity, as it involves multiple signaling pathways and also resembles many aspects of drug-induced liver injury; however, the exact mode of cell death is not completely understood [65]. Recent studies have demonstrated a role of ER stress in acetaminophen-induced liver toxicity [65][66][67][68]. A sublethal dose of acetaminophen results in activation of ER stress markers include ATF6 and CHOP.…”

Section: Er Stress and Drug-induced Liver Toxicity Acetaminophenmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Chen

Melchior

Guo

2014

Journal of Environmental Science and Health, Part C

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Liver injury resulting from exposure to drugs and environmental chemicals is a major health problem. Endoplasmic reticulum stress (ER stress) is considered to be an important factor in a wide range of diseases, such as cancer, neurological and cardiovascular disease, diabetes, and inflammatory diseases. The role of ER stress in drug-induced and environmental toxicant-induced liver toxicity has been underestimated in the past; emerging evidence indicates that ER stress makes a substantial contribution to the pathogenesis of drug-induced liver toxicity. In this review, we summarize current knowledge on drugs and environmental toxicants that trigger ER stress in liver and on the underlying molecular mechanisms. We also discuss experimental approaches for ER stress studies.

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“…Indeed, it has been reported that APAP induced severe GSH depletion, lipid peroxidation, and an oxidative shift of the ER oxidoreductases ERp72 and PDI in liver microsomes (Nagy et al. 2007; Letelier et al. 2011).…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

188

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Acetaminophen induces ER dependent signaling in mouse liver

Cited by 94 publications

References 35 publications

Ferroptosis is Involved in Acetaminophen Induced Cell Death

Ferroptosis is Involved in Acetaminophen Induced Cell Death

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

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