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

Chen, Si; Melchior, William B.; Guo, Lei

doi:10.1080/10590501.2014.881648

Cited by 50 publications

(40 citation statements)

References 144 publications

(184 reference statements)

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“…2013; Chen et al. 2014). Notably, ER stress is leading to the activation of the so‐called unfolded protein response (UPR), the role of which is to maintain protein homeostasis by decreasing the load of unfolded proteins and increasing the protein folding capacity (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

189

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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Section: Introductionmentioning

confidence: 99%

“…The role and mechanisms of ER stress in sertraline and troglitazone‐induced hepatotoxicity have been discussed in a recent review (Chen et al. 2014). Hepatic ER stress has also been detected in a mouse model of liver toxicity induced by the diuretic drug furosemide (Table 1) (Qu et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

189

161

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“…These diseases include, but are not limited to, neurological (Alzheimer's disease, Parkinson's disease), kidney, lung, and cardiovascular diseases, diabetes, obesity/metabolic syndrome, inflammatory diseases and cancer [23]. In addition, environmental toxicants as well as drugs were related to ER stress in the last reports.…”

Section: Endoplasmic Reticulum (Er) Stressmentioning

confidence: 99%

“…The HIV-protease inhibitors, atazanavir and ritonavir were shown to induce both ER stress and apoptosis. Moreover, the mechanisms involved in the liver toxicity of anti-diabetic drug troglitazone, include mitochondrial dysfunction, apoptosis, disruption of calcium hemostasis, oxidative stress, and ER stress [23]. Although the most important mechanism for sertaline-induced liver toxicity is mitochondrial dysfunction and apoptosis, ER stress was found to contribute to its liver toxicity [29].…”

Section: Endoplasmic Reticulum (Er) Stressmentioning

confidence: 99%

“…ER stress is an exciting area of research in liver injury, although available data mostly comes from other experimental systems. The stressed ER exhibits an imbalance between unfolded proteins and mature proteins, activating a series of compensatory responses, collectively termed as "unfolded protein response" [23][24][25]. Three ER membrane-localized proteins are considered as 'sensors' of ER stress: inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-activated (PKR)-like ER kinase (PERK) [26].…”

Section: Endoplasmic Reticulum (Er) Stressmentioning

confidence: 99%

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Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

Erkekoğlu¹

2015

MOJT

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Despite recent advances in drug development technologies, some drugs continue to be withdrawn from the market because of their late hepatotoxic effects. Drugs can cause liver toxicity through several molecular mechanisms, most of which need to be clarified by further research. Newly found drug-induced liver injury (DILI)-mechanisms like endoplasmic reticulum stress should also be considered while evaluating drug toxicity. New drugs launched in the market should be tested particularly for hepatotoxicity by using hepatic cell cultures and animal models continuously. Future research should target patients in the post-marketing phase in order to provide more evidence grounds to the clinical safety of potential drugs of high propensity of DILI. This review aims to draw the attention to the issue of cellular and molecular aspects of liver toxicity induced by drugs and address DILI as a potential clinical problem that needs further investigation.

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Cantharidin‐induced LO2 cell autophagy and apoptosis via endoplasmic reticulum stress pathway in vitro

Liu

Duan

Zhang

et al. 2020

J of Applied Toxicology

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Cantharidin (CTD), an important active compound derived from the traditional Chinese medicine Mylabris (also called Banmao), has been used in the treatment of diseases such as tumors and dermatosis. However, Mylabris has been shown to induce hepatotoxicity in clinical practice and animal experiments, limiting its use. Further, a detailed mechanism underlying CTD‐induced hepatotoxicity has not been determined. In the present study, we aimed to explore the effect of endoplasmic reticulum stress (ERS), autophagy, and apoptosis on CTD‐induced hepatotoxicity. We found that CTD could inhibit the proliferation of LO2 cells; increase alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and malondialdehyde levels; and reduce glutathione peroxidase and superoxide dismutase activities. Western blotting showed that low concentrations of CTD induced the expressions of ERS‐related proteins [GRP78, ATF4, PERK, p‐PERK, XBP1–1 s, and CHOP], but high concentrations of CTD inhibited their expressions. Furthermore, high concentrations of CTD activated autophagy (LC3, Beclin‐1, Atg3, Atg4A, Atg4B, and Atg7), induced the expressions of apoptotic proteins (Bax/Bcl‐2 and caspase‐3), and increased LO2 toxicity. Taken together, these results indicated that CTD can induce LO2 cytotoxicity by inhibiting ERS and inducing autophagy and apoptosis, which provides a scientific basis for CTD‐induced hepatotoxicity.

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

Cited by 50 publications

References 144 publications

Role of endoplasmic reticulum stress in drug‐induced toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms

Cantharidin‐induced LO2 cell autophagy and apoptosis via endoplasmic reticulum stress pathway in vitro

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