Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Kuijper, Isoude A.; Yang, Huan; Water, Bob van de; Beltman, Joost B.

doi:10.1080/17425255.2017.1234607

Cited by 17 publications

(7 citation statements)

References 118 publications

(177 reference statements)

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“…Computational approaches are becoming increasingly important for safety evaluation of chemicals, and dynamical models represent one of the approaches that will be useful for that purpose in the future ( Kuijper et al, 2017 ). Such models represent a so-called quantitative adverse outcome pathway (qAOP) or part thereof.…”

Section: Discussionmentioning

confidence: 99%

“…A promising way forward is to utilize high-throughput measurement techniques to collect dynamic data on the mitochondrial membrane potential ( Wink et al, 2017 ). Moreover, obtaining a quantitative, mechanistic understanding of such in vitro experiments is desirable ( National Research Council, 2007 ), which can be achieved through application of dynamic modeling in the form of ordinary differential equation (ODE) models to describe experimental measurements ( Kuijper et al, 2017 ; van Riel, 2006 ; Yang et al, 2020 ). Such mechanistic models can be utilized to generate hypotheses and to formally test whether a data set is consistent with these hypotheses ( van Riel, 2006 ; Brodland, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors

et al. 2021

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Mitochondria are the main bioenergetic organelles of cells. Exposure to chemicals targeting mitochondria therefore generally results in the development of toxicity. The cellular response to perturbations in cellular energy production is a balance between adaptation, by reorganisation and organelle biogenesis, and sacrifice, in the form of cell death. In homeostatic conditions, aerobic mitochondrial energy production requires the maintenance of a mitochondrial membrane potential (MMP). Chemicals can perturb this MMP, and the extent of this perturbation depends both on the pharmacokinetics of the chemicals and on downstream MMP dynamics. Here we obtain a quantitative understanding of mitochondrial adaptation upon exposure to various mitochondrial respiration inhibitors by applying mathematical modeling to partially published high-content imaging time-lapse confocal imaging data, focusing on MMP dynamics in HepG2 cells over a period of 24 h. The MMP was perturbed using a set of 24 compounds, either acting as uncoupler or as mitochondrial complex inhibitor targeting complex I, II, III or V. To characterize the effect of chemical exposure on MMP dynamics, we adapted an existing differential equation model and fitted this model to the observed MMP dynamics. Complex III inhibitor data were better described by the model than complex I data. Incorporation of pharmacokinetic decay into the model was required to obtain a proper fit for the uncoupler FCCP. Furthermore, oligomycin (complex V inhibitor) model fits were improved by either combining pharmacokinetic (PK) decay and ion leakage or a concentration-dependent decay. Subsequent mass spectrometry measurements showed that FCCP had a significant decay in its PK profile as predicted by the model. Moreover, the measured oligomycin PK profile exhibited only a limited decay at high concentration, whereas at low concentrations the compound remained below the detection limit within cells. This is consistent with the hypothesis that oligomycin exhibits a concentration-dependent decay, yet awaits further experimental verification with more sensitive detection methods. Overall, we show that there is a complex interplay between PK and MMP dynamics within mitochondria and that data-driven modeling is a powerful combination to unravel such complexity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors

et al. 2021

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“…Evidence shows that hepatocyte apoptosis contributes to a number of liver diseases, including alcohol-induced liver disease, viral hepatitis, cholestatic liver disease, non-alcoholic fatty liver disease, and Wilson’s disease 25 . DDR signalling is another fundamental pathway affecting human and animal diseases, such as liver cancer 26 , and which has been found activated in rodent liver upon feeding with cell-damaging agents 27–29 . The unfolded protein response pathway is also activated upon cellular stress or exposure to certain drugs 30 , and is related to an accumulation of unfolded or wrongly folded proteins within the endoplasmic reticulum (ER) 31 .…”

Section: Discussionmentioning

confidence: 99%

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

Stein

Ran

Bohmer

et al. 2019

Sci Rep

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In a recent one-year feeding study, we observed no adverse effects on tissue level in organs of rats fed with the genetically-modified maize MON810. Here, we assessed RNA expression levels of 86 key genes of the apoptosis-, NF-кB-, DNA-damage response (DDR)-, and unfolded-protein response (UPR) pathways by RT-qPCR in the rat liver. Male and female rats were fed either with 33% MON810 (GMO), isogenic- (ISO), or conventional maize (CONV) and RNAs were quantified from eight rats from each of the six feeding groups. Only Birc2 transcript showed a significant (p ≤ 0.05) consistent difference of ≥1.5-fold between the GMO and ISO groups in both sexes. Unsupervised cluster analysis showed a strong separation of male and female rats, but no clustering of the feeding groups. Individual analysis of the pathways did not show any clustering of the male or female feeding groups either, though transcript levels of UPR pathway-associated genes caused some clustering of the male GMO and CONV feeding group samples. These differences were not seen between the GMO and ISO control or within the female cohort. Our data therefore does not support an adverse effect on rat liver RNA expression through the long-term feeding of MON810 compared to isogenic control maize.

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“…A large variety of these substances, either directly or in the course of their activation, contributes to the generation of oxidative stress. Systematic integration of quantitative and qualitative information into the framework of an adverse outcome pathway revealed the causal involvement of oxidative stress in liver pathologies such as drug-induced liver injury, alcoholic liver disease, cholestatic liver injury, and nonalcoholic fatty liver disease (Kuijper et al 2017 ; Khadka et al 2020 ; Horvat et al 2017 ; Vinken et al 2013 ). Many approaches have been attempted in order to alleviate or prevent liver disease via the reduction of oxidative stress (Li et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes

et al. 2021

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Toxicity is not only a function of damage mechanisms, but is also determined by cellular resilience factors. Glutathione has been reported as essential element to counteract negative influences. The present work hence pursued the question how intracellular glutathione can be elevated transiently to render cells more resistant toward harmful conditions. The antibiotic nitrofurantoin (NFT) was identified to stimulate de novo synthesis of glutathione in the human hepatoma cell line, HepG2, and in primary human hepatocytes. In intact cells, activation of NFT yielded a radical anion, which subsequently initiated nuclear-factor-erythroid 2-related-factor-2 (Nrf2)-dependent induction of glutamate cysteine ligase (GCL). Application of siRNA-based intervention approaches confirmed the involvement of the Nrf2-GCL axis in the observed elevation of intracellular glutathione levels. Quantitative activation of Nrf2 by NFT, and the subsequent rise in glutathione, were similar as observed with the potent experimental Nrf2 activator diethyl maleate. The elevation of glutathione levels, observed even 48 h after withdrawal of NFT, rendered cells resistant to different stressors such as the mitochondrial inhibitor rotenone, the redox cycler paraquat, the proteasome inhibitors MG-132 or bortezomib, or high concentrations of NFT. Repurpose of the antibiotic NFT as activator of Nrf2 could thus be a promising strategy for a transient and targeted activation of the endogenous antioxidant machinery.

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Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

Cited by 17 publications

References 118 publications

Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors

Dynamic Modeling of Mitochondrial Membrane Potential Upon Exposure to Mitochondrial Inhibitors

Expression profiling of key pathways in rat liver after a one-year feeding trial with transgenic maize MON810

Stimulation of de novo glutathione synthesis by nitrofurantoin for enhanced resilience of hepatocytes

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