ArticleScientific reports2016
Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 97 citations in OpenAlex.
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- Neurovascular Signaling at the Gliovascular Interface: From Flow Regulation to Cognitive Energy Coupling.International journal of molecular sciences · 2025Review
- Cell-based approaches for the mechanistic understanding of drug-induced cholestatic liver injury.Archives of toxicology · 2025Review
- Mechanisms of drug induced liver injury.Cellular and molecular life sciences : CMLS · 2025Review
- Activation of S1PR2 on macrophages and the hepatocyte S1PR2/RhoA/ROCK1/MLC2 pathway in vanishing bile duct syndrome.PloS one · 2025Article
- Sympathetic nerve block as an add-on therapy for intervention and prevention of cerebral vasospasm after subarachnoid hemorrhage.Frontiers in neurology · 2025Review
- Role of Redox Homeostasis in the Communication Between Brain and Liver Through Extracellular Vesicles.Antioxidants (Basel, Switzerland) · 2024Review
- Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice.Scientific reports · 2024Article
- Lung cancer cell-intrinsic IL-15 promotes cell migration and sensitizes murine lung tumors to anti-PD-L1 therapy.Biomarker research · 2024Article
- Article
- Mitigation of intrahepatic cholestasis induced by 17α-ethinylestradiol via nanoformulation of Silybum marianum L.BMC complementary medicine and therapies · 2024Article
- Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Quantitative understanding of HepaRG cells during drug-induced intrahepatic cholestasis through changes in bile canaliculi dynamics.Pharmacology research & perspectives · 2022Article
- Automated Analysis of Acetaminophen Toxicity on 3D HepaRG Cell Culture in Microbioreactor.Bioengineering (Basel, Switzerland) · 2022Article
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- Efficient Generation of Functional Hepatocytes from Human Induced Pluripotent Stem Cells for Disease Modeling and Disease Gene Discovery.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Tight junction stabilization prevents HepaRG cell death in drug-induced intrahepatic cholestasis.Biology open · 2021Article
- The Impact of Modern Chemotherapy and Chemotherapy-Associated Liver Injuries (CALI) on Liver Function: Value of 99mTc-Labelled-Mebrofenin SPECT-Hepatobiliary Scintigraphy.Annals of surgical oncology · 2021Article
- Biogenesis of Extracellular Vesicles.Sub-cellular biochemistry · 2021Article
- Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells.American journal of obstetrics and gynecology · 2020Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intrahepatic cholestasis represents a frequent manifestation of drug-induced liver injury; however, the mechanisms underlying such injuries are poorly understood. In this study of human HepaRG and primary hepatocytes, we found that bile canaliculi (BC) underwent spontaneous contractions, which are essential for bile acid (BA) efflux and require alternations in myosin light chain (MLC2) phosphorylation/dephosphorylation. Short exposure to 6 cholestatic compounds revealed that BC constriction and dilation were associated with disruptions in the ROCK/MLCK/myosin pathway. At the studied concentrations, cyclosporine A and chlorpromazine induced early ROCK activity, resulting in permanent MLC2 phosphorylation and BC constriction. However, fasudil reduced ROCK activity and caused rapid, substantial and permanent MLC2 dephosphorylation, leading to BC dilation. The remaining compounds (1-naphthyl isothiocyanate, deoxycholic acid and bosentan) caused BC dilation without modulating ROCK activity, although they were associated with a steady decrease in MLC2 phosphorylation via MLCK. These changes were associated with a common loss of BC contractions and failure of BA clearance. These results provide the first demonstration that cholestatic drugs alter BC dynamics by targeting the ROCK/MLCK pathway; in addition, they highlight new insights into the mechanisms underlying bile flow failure and can be used to identify new predictive biomarkers of drug-induced cholestasis.
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