Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury

Copple, Ian M.; Hollander, Wouter den; Callegaro, Giulia; Mutter, Fiona; Maggs, James L.; Schofield, Amy; Rainbow, Lucille; Fang, Yongxiang; Sutherland, Jeffrey J.; Ellis, Ewa; Ingelman‐Sundberg, Magnus; Fenwick, Stephen; Goldring, Christopher E.; Water, Bob van de; Stevens, James; Park, B. Kevin

doi:10.1007/s00204-018-2354-1

Cited by 26 publications

(15 citation statements)

References 31 publications

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“…In parallel, the availability of advanced high-throughput approaches was exploited to increase the applicability domains and throughput levels of the test methods. Screening transcriptomics data were provided from hepatic (Albrecht et al 2019 ; Campos et al 2020 ; Copple et al 2019 ; Ramirez et al 2018 ), renal (Limonciel et al 2018a , b ) and neuronal (Delp et al 2019 ) cell systems. High-content imaging was expanded to complex toxicological endpoints, such as DART (Dreser et al 2020 ; Nyffeler et al 2018 ) and systemic RDT with the establishment of novel fluorescent protein reporter cell lines (Bischoff et al 2019 ; Schimming et al 2019 ; Wink et al 2018 ; Yang et al 2020 ).…”

Section: The Repository Of Nams Available For Nam-enhanced Raxmentioning

confidence: 99%

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

et al. 2020

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In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

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Section: The Repository Of Nams Available For Nam-enhanced Raxmentioning

confidence: 99%

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

et al. 2020

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“…This means that it may be possible to define sets of genes that indicate the activation of a KE within a relevant concentration range. One approach to do this is to apply weighted gene co-regulated network (WGCN) analysis (Copple et al 2019 ). If this is calibrated in a way to find a threshold of activation that correlates with adversity, WGCN analysis might provide a general method to test for AOP activation.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

et al. 2021

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Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.

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“…NCF2 is the cytosolic subunit of the multi-protein NADPH oxidase complex [154], while PDLIM1 (also known as mystique or CLP36) is a nuclear protein involved in the regulation of NF-κB activity [155]. Importantly, NRF2 activity is able to regulate the expression of NCF2 [156,157] and PDLIM1 [158], with the second acquiring particular relevance as it is considered a biomarker of cardiomyocyte oxidative status (153) and participates in the regenerative process of peripheral neurons of the dorsal root ganglia [159]. Thus, monitoring PDLIM1 expression in blood could provide clues on the effectiveness of treatments in the two tissues mostly affected in FA.…”

Section: Nrf2 Signaling Network As a Biomarker In The Evaluation Of Fmentioning

confidence: 99%

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

Rosa

Bertini

Piemonte

2020

IJMS

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Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

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Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury

Cited by 26 publications

References 31 publications

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

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