ArticleToxicological sciences : an official journal of the Society of Toxicology2018
miR-122 Release in Exosomes Precedes Overt Tolvaptan-Induced Necrosis in a Primary Human Hepatocyte Micropatterned Coculture Model.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 54 citations in OpenAlex.
- Tolvaptan safety in autosomal-dominant polycystic kidney disease; a focus on idiosyncratic drug-induced liver injury liabilities.Toxicological sciences : an official journal of the Society of Toxicology · 2025Review
- Evaluation of tolvaptan-associated hepatic disorder using different national pharmacovigilance databases.Scientific reports · 2024Article
- MicroRNAs in Anticancer Drugs Hepatotoxicity: From Pathogenic Mechanism and Early Diagnosis to Therapeutic Targeting by Natural Products.Current pharmaceutical biotechnology · 2024Review
- Comparison of methods of isolating extracellular vesicle microRNA from HepG2 cells for High-throughput sequencing.Frontiers in molecular biosciences · 2022Article
- Protective effects of exosomes derived from lyophilized porcine liver against acetaminophen damage on HepG2 cells.BMC complementary medicine and therapies · 2021Article
- Latest impact of engineered human liver platforms on drug development.APL bioengineering · 2021Review
- Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice.Antioxidants (Basel, Switzerland) · 2021Review
- Methodological considerations for measuring biofluid-based microRNA biomarkers.Critical reviews in toxicology · 2021Article
- Characterization of primary mouse hepatocyte spheroids as a model system to support investigations of drug-induced liver injury.Toxicology in vitro : an international journal published in association with BIBRA · 2021Article
- Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression.Journal of pharmaceutical sciences · 2021Article
- Review
- Tolvaptan- and Tolvaptan-Metabolite-Responsive T Cells in Patients with Drug-Induced Liver Injury.Chemical research in toxicology · 2020Article
- Using Machine Learning Methods and Structural Alerts for Prediction of Mitochondrial Toxicity.Molecular informatics · 2020Article
- Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling.Pharmaceutical research · 2020Article
- Article
- Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Drug-Induced Liver Injury: Highlights of the Recent Literature.Drug safety · 2019Review
- Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives.Frontiers in pharmacology · 2019Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Idiosyncratic drug-induced liver injury (IDILI) is thought to often result from an adaptive immune attack on the liver. However, it has been proposed that the cascade of events culminating in an adaptive immune response begins with drug-induced hepatocyte stress, release of exosomal danger signals, and innate immune activation, all of which may occur in the absence of significant hepatocelluar death. A micropatterned coculture model (HepatoPac) was used to explore the possibility that changes in exosome content precede overt necrosis in response to the IDILI drug tolvaptan. Hepatocytes from 3 human donors were exposed to a range of tolvaptan concentrations bracketing plasma Cmax or DMSO control continuously for 4, 24, or 72 h. Although alanine aminotransferase release was not significantly affected at any concentration, tolvaptan exposures at approximately 30-fold median plasma Cmax resulted in increased release of exosomal microRNA-122 (miR-122) into the medium. Cellular imaging and microarray analysis revealed that the most significant increases in exosomal miR-122 were associated with programmed cell death and small increases in membrane permeability. However, early increases in exosome miR-122 were more associated with mitochondrial-induced apoptosis and oxidative stress. Taken together, these data suggest that tolvaptan treatment induces cellular stress and exosome release of miR-122 in primary human hepatocytes in the absence of overt necrosis, providing direct demonstration of this with a drug capable of causing IDILI. In susceptible individuals, these early events may occur at pharmacologic concentrations of tolvaptan and may promote an adaptive immune attack that ultimately results in clinically significant liver injury.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.