Integrative cross-omics analysis in primary mouse hepatocytes unravels mechanisms of cyclosporin A-induced hepatotoxicity

Hof, Wim F.P.M. Van den; Summeren, Anke Van; Lommen, Arjen; Coonen, Maarten; Brauers, Karen; Herwijnen, Marcel van; Wodzig, Will K. W. H.; Kleinjans, Jos

doi:10.1016/j.tox.2014.06.003

Cited by 22 publications

(11 citation statements)

References 40 publications

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“…Multi‐omics in vitro approaches also facilitate novel insight into ADR pathogenicity. For example, single and integrative transcriptomic, proteomic and metabolomics analyses of mouse hepatocytes, following exposure to the prototypical hepatotoxicant cyclosporin A, revealed mechanisms underlying cyclosporin A cholestasis including endoplasmic reticulum stress …”

Section: Systems Pharmacology For Parsing Interindividual Drug Variabmentioning

confidence: 99%

“…For example, single and integrative transcriptomic, proteomic and metabolomics analyses of mouse hepatocytes, following exposure to the prototypical hepatotoxicant cyclosporin A, revealed mechanisms underlying cyclosporin A cholestasis including endoplasmic reticulum stress. 75 Thirdly, a transition into an era of Big Data is rapidly occurring with data storage in large, often publically available online repositories. These data are being amassed from multiple sources including the increasing use of omics technologies to analyze patient-derived biological samples, systematic cell line transcriptomic profiling after genetic or pharmacological perturbation, systematic investigations of biological molecule interactions (e.g., gene-regulatory and protein-protein interactions) and increasing drug-centric data (e.g., phenotype and physiochemical data).…”

Section: Pharmacologically-orientated Systems Biologymentioning

confidence: 99%

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Parsing interindividual drug variability: an emerging role for systems pharmacology

Turner

Park

Pirmohamed

2015

WIREs Mechanisms of Disease

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There is notable interindividual heterogeneity in drug response, affecting both drug efficacy and toxicity, resulting in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is at the forefront of research to understand interindividual drug response variability, but although many genotype-drug response associations have been identified, translation of pharmacogenomic associations into clinical practice has been hampered by inconsistent findings and inadequate predictive values. These limitations are in part due to the complex interplay between drug-specific, human body and environmental factors influencing drug response and therefore pharmacogenomics, whilst intrinsically necessary, is by itself unlikely to adequately parse drug variability. The emergent, interdisciplinary and rapidly developing field of systems pharmacology, which incorporates but goes beyond pharmacogenomics, holds significant potential to further parse interindividual drug variability. Systems pharmacology broadly encompasses two distinct research efforts, pharmacologically-orientated systems biology and pharmacometrics. Pharmacologically-orientated systems biology utilizes high throughput omics technologies, including next-generation sequencing, transcriptomics and proteomics, to identify factors associated with differential drug response within the different levels of biological organization in the hierarchical human body. Increasingly complex pharmacometric models are being developed that quantitatively integrate factors associated with drug response. Although distinct, these research areas complement one another and continual development can be facilitated by iterating between dynamic experimental and computational findings. Ultimately, quantitative data-derived models of sufficient detail will be required to help realize the goal of precision medicine. WIREs Syst Biol Med 2015, 7:221–241. doi: 10.1002/wsbm.1302

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Section: Systems Pharmacology For Parsing Interindividual Drug Variabmentioning

confidence: 99%

Section: Pharmacologically-orientated Systems Biologymentioning

confidence: 99%

Parsing interindividual drug variability: an emerging role for systems pharmacology

Turner

Park

Pirmohamed

2015

WIREs Mechanisms of Disease

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“…By causing global inhibition of T cells, the host's innate immune system becomes severely impaired [1][2][3][4][5]. For instance, cyclosporine, a calcineurin inhibitor, can cause immunotoxicity through the destruction of liver tissue [1,6]. In addition, antiproliferatives, such as MMF and mTOR inhibitors, cause leukopenia and can delay the functionality of the graft [2,3].…”

Section: Introductionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells

Sido

Nagarkatti

2015

Journal of Leukocyte Biology

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Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2(k) splenocytes into H-2(b) mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection-indicator cytokines, including IL-2 and IFN-γ. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection.

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“…Metabolomics can provide appraisal of a biological system's biochemical and physiological status, e.g., with cell culture analysis [14,15]. Of all omics technologies, metabolomics is thought to best represent "classical toxicology" [16].…”

Section: Introductionmentioning

confidence: 99%

Metabolomic Profile of Primary Turkey and Rat Hepatocytes and Two Cell Lines after Chloramphenicol Exposure

Radko

Śniegocki

Sell

et al. 2019

Animals

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Simple Summary: The use of cell cultures can be an important alternative for animal experiments. Therefore, it seems reasonable to use in vitro models to compare the liver metabolism of a drug in different animal species. Chloramphenicol is an effective broad-spectrum antibiotic used in human and pets. The toxicity of chloramphenicol is complex and differs among animal species mainly depending on the biotransformation. The purpose of this study was to assess chloramphenicol metabolism on its cytotoxicity in primary turkey and rat hepatocyte cultures, also in human hepatoma (HepG2) cells and nonhepatic, Balb/c 3T3 fibroblasts. To the best of our knowledge, this is the first report of differences in chloramphenicol metabolism in primary turkey and rat hepatocyte cultures. The two metabolites of the drug were detected in turkey and rat hepatocyte cultures. The amount of one metabolite of chloramphenicol was closely related to the cytotoxicity of the drug. The primary turkey and rat hepatocyte cultures were more sensitive to chloramphenicol than HepG2 cells and Balb/c 3T3 fibroblasts. The primary hepatocyte cultures represent valuable tools with which to study the biotransformation of xenobiotics and determine species differences in their metabolism and toxicity. Abstract:The purpose of this study was to assess the formation of chloramphenicol metabolites in primary turkey and rat hepatocyte cultures and human hepatoma (HepG2) cells and nonhepatic, Balb/c 3T3 fibroblasts. Additionally, the cytotoxicity of the drug was assessed through three biochemical endpoints: mitochondrial and lysosomal activity and cellular membrane integrity after 24 and 48 h exposure. The two metabolites of the drug, chloramphenicol glucuronide and nitroso-chloramphenicol, were detected to the greatest extent in both primary hepatocyte cultures by liquid chromatography-tandem mass spectrometry. Toxic nitroso-chloramphenicol was the main metabolite in the primary turkey hepatocyte cultures, but it was not in the primary rat hepatocyte cultures. The most affected endpoint in turkey and rat hepatocyte cultures was the disintegration of the cellular membrane, but in the cell lines, mitochondrial and lysosomal activities underwent the greatest change. The primary hepatocyte cultures represent valuable tools with which to study the species differences in the biotransformation and toxicity of drugs. To the best of our knowledge, this is the first report of differences in chloramphenicol metabolism in primary turkey and rat hepatocyte cultures.

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Integrative cross-omics analysis in primary mouse hepatocytes unravels mechanisms of cyclosporin A-induced hepatotoxicity

Cited by 22 publications

References 40 publications

Parsing interindividual drug variability: an emerging role for systems pharmacology

Parsing interindividual drug variability: an emerging role for systems pharmacology

Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells

Metabolomic Profile of Primary Turkey and Rat Hepatocytes and Two Cell Lines after Chloramphenicol Exposure

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