ArticleToxicological sciences : an official journal of the Society of Toxicology2014
Different dose-dependent mechanisms are involved in early cyclosporine a-induced cholestatic effects in hepaRG cells.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 67 citations in OpenAlex.
- A collagen hydrogel-based 3D Heparg model for enhanced hepatocyte function and assessment of cholestatic drug-induced liver injury.Archives of toxicology · 2026Article
- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- Involvement of oxidative species in cyclosporine-mediated cholestasis.Frontiers in pharmacology · 2022Review
- In-Depth Study ofBioMed research international · 2022Article
- Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals.International journal of molecular sciences · 2021Article
- The Food Contaminants Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis Structure-Dependently in the Human Hepatoma Cell Line HepaRG.Foods (Basel, Switzerland) · 2021Article
- Impairment of bile acid metabolism by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in human HepaRG hepatoma cells.Archives of toxicology · 2020Article
- Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury.Archives of toxicology · 2020Article
- Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models.Nature reviews. Drug discovery · 2020Review
- Epistane, an anabolic steroid used for recreational purposes, causes cholestasis with elevated levels of cholic acid conjugates, by upregulating bile acid synthesis (CYP8B1) and cross-talking with nuclear receptors in human hepatocytes.Archives of toxicology · 2020Article
- ZIP14 is degraded in response to manganese exposure.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2019Article
- Article
- Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.Scientific reports · 2017Article
- Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.Scientific reports · 2017Article
- Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability.Scientific reports · 2016Article
- Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs.Scientific reports · 2016Article
- Bile Acid-Induced Toxicity in HepaRG Cells Recapitulates the Response in Primary Human Hepatocytes.Basic & clinical pharmacology & toxicology · 2016Article
- Role of endoplasmic reticulum stress in drug-induced toxicity.Pharmacology research & perspectives · 2016Review
- A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen.Toxicology and applied pharmacology · 2016Article
- Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mechanisms involved in drug-induced cholestasis in humans remain poorly understood. Although cyclosporine A (CsA) and tacrolimus (FK506) share similar immunosuppressive properties, only CsA is known to cause dose-dependent cholestasis. Here, we have investigated the mechanisms implicated in early cholestatic effects of CsA using the differentiated human HepaRG cell line. Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 min and 1 h respectively after addition of 10μM CsA; it peaked at around 2 h and was reversible. These early effects were associated with generation of oxidative stress and deregulation of cPKC pathway. At higher CsA concentrations (≥50μM) alterations of efflux and uptake activities were enhanced and became irreversible, pericanalicular F-actin microfilaments were disorganized and bile canaliculi were constricted. These changes were associated with induction of endoplasmic reticulum stress that preceded generation of oxidative stress. Concentration-dependent changes were observed on total bile acid disposition, which were characterized by an increase and a decrease in culture medium and cells, respectively, after a 24-h treatment with CsA. Accordingly, genes encoding hepatobiliary transporters and bile acid synthesis enzymes were differently deregulated depending on CsA concentration. By contrast, FK506 induced limited effects only at 25-50μM and did not alter bile canaliculi. Our data demonstrate involvement of different concentration-dependent mechanisms in CsA-induced cholestasis and point out a critical role of endoplasmic reticulum stress in the occurrence of the major cholestatic features.
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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 OpenQuestion graph.