Screening for Drug-Induced Hepatotoxicity in Primary Mouse Hepatocytes Using Acetaminophen, Amiodarone, and Cyclosporin A as Model Compounds: An Omics-Guided Approach

Summeren, Anke Van; Renes, Johan; Lizarraga, Daneida; Bouwman, Freek G.; Noben, Jean-Paul; Delft, J.H.M. van; Kleinjans, Jos; Mariman, E.C.M.

doi:10.1089/omi.2012.0079

Cited by 21 publications

(23 citation statements)

References 47 publications

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“…2012; van Summeren et al. 2013). Actually, some data in mice indicated that ER stress was a relatively late event after APAP intoxication (500 mg/kg), being significant only 12 hours following APAP administration (Hur et al.…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

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%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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“…The proteins differentially expressed after exposure to CsA in HepG2 and primary mouse hepatocytes, were retrieved from previous studies [9,10]. The Panther classification system (http:// www.pantherdb.org) was used to compare the effect of CsA upon the protein expression in HepG2, primary mouse hepatocytes and in vivo mouse liver.…”

Section: Functional Classificationmentioning

confidence: 99%

“…Previously we investigated the proteome of HepG2 cells and primary mouse hepatocytes after exposure to three well-defined hepatotoxicants [9,10]. These were acetaminophen, amiodarone and cyclosporin A (CsA), of which CsA generated the most prominent response.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we want to compare these results with our previous in vitro studies with HepG2 and primary mouse hepatocytes [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…The results from our previous studies with HepG2 [9] and primary mouse hepatocytes [10] were used to establish an in vitroin vivo comparison of CsA-induced protein expression profiles.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro, In Vivo Comparison of Cyclosporin A Induced Hepatic Protein Expression Profiles

Bouwman¹,

Summeren²,

Kienhuis³

et al. 2016

J Clinic Toxicol

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To reduce the amount of laboratory animals which are used to analyze hepatotoxic properties of chemicals and drugs, the development of alternative in vitro models is necessary. Ideally these in vitro models reflect the in vivo toxicological response and cholestasis. In this study the protein expression in livers from C57BL/6 mice after cyclosporin A-induced cholestasis was analyzed. After 25 days of a daily cyclosporine A treatment the cholestatic phenotype was established. An in vitro to this in vivo study comparison was made by using the results of our previous studies with HepG2 and primary mouse hepatocytes. The in vivo proteomics data show cyclosporin Ainduced oxidative stress and mitochondrial dysfunction was actually induced, leading to a decreased mitochondrial ATP production and an altered urea cycle. These processes were also altered by cyclosporin A in the in vitro models HepG2 and primary mouse hepatocytes. In addition, detoxification enzymes like methyl-and glutathione-Stransferases were differentially expressed after cyclosporin A treatment. Changes in these detoxification enzymes were mainly detected in vivo, though primary mouse hepatocytes show a differential expression of some of these enzymes. By means of a functional classification of differentially expressed proteins we demonstrated similarities and differences between in vitro and in vivo models in the proteome response of cyclosporin A-induced hepatotoxicity.

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In vitro assessment of hepatotoxicity by metabolomics: a review

et al. 2018

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Omics technologies, and in particular metabolomics, have received an increasing attention during the assessment of hepatotoxicity in vitro. However, at present, a consensus on good metabolomics practices has yet to be reached. Therefore, in this review, a range of experimental approaches, applied methodologies, and data processing workflows are compared and critically evaluated. Experimental designs among the studies are similar, reporting the use of primary hepatocytes or hepatic cell lines as the most frequently used cell sources. Experiments are usually conducted in short time-frames (< 48 h) at sub-toxic dosages. Applied sample preparations are protein precipitation or Bligh-and-Dyer extraction. Most analytical platforms rely on chromatographic separations with mass spectrometric detection using high-resolution instruments. Untargeted metabolomics was typically used to allow the simultaneous detection of several classes of the metabolome, including endogenous metabolites that are not initially linked to toxicity. This non-biased detection platform is a valuable tool for generating hypothesis-based mechanistic research. The most frequently reported metabolites that are altered under toxicological impulses are alanine, lactate, and proline, which are often correlated. Other unspecific biomarkers of hepatotoxicity in vitro are the down-regulation of choline, glutathione, and 3-phospho-glycerate. Disruptions on the Krebs cycle are associated with increased glutamate, tryptophan, and valine. Phospholipid alterations are described in steatosis, lipo-apoptosis, and oxidative stress. Although there is a growing trend towards quality control, data analysis procedures do often not follow good contemporary metabolomics practices, which include feature filtering, false-discovery rate correction, and reporting the confidence of metabolite annotation. The currently annotated biomarkers can be used to identify hepatotoxicity in general and provide, to a certain extent, a tool for mechanistic distinction.

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Screening for Drug-Induced Hepatotoxicity in Primary Mouse Hepatocytes Using Acetaminophen, Amiodarone, and Cyclosporin A as Model Compounds: An Omics-Guided Approach

Cited by 21 publications

References 47 publications

Role of endoplasmic reticulum stress in drug‐induced toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

In Vitro, In Vivo Comparison of Cyclosporin A Induced Hepatic Protein Expression Profiles

In vitro assessment of hepatotoxicity by metabolomics: a review

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