ArticleScientific reports2017
Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 26 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
- Article
- Identification of flucloxacillin-modified hepatocellular proteins: implications in flucloxacillin-induced liver injury.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance.Cancers · 2020Article
- Article
- Heat shock protein 27 promotes cell cycle progression by down-regulating E2F transcription factor 4 and retinoblastoma family protein p130.The Journal of biological chemistry · 2018Article
- In vitro prediction of drug-induced cholestatic liver injury: a challenge for the toxicologist.Archives of toxicology · 2018Article
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Authors and funding
7 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The penicillinase-resistant antibiotics (PRAs), especially the highly prescribed flucloxacillin, caused frequent liver injury via mechanisms that remain largely non-elucidated. We first showed that flucloxacillin, independently of cytotoxicity, could exhibit cholestatic effects in human hepatocytes in the absence of an immune reaction, that were typified by dilatation of bile canaliculi associated with impairment of the Rho-kinase signaling pathway and reduced bile acid efflux. Then, we analyzed the sequential molecular events involved in flucloxacillin-induced cholestasis. A crucial role of HSP27 by inhibiting Rho-kinase activity was demonstrated using siRNA and the specific inhibitor KRIBB3. HSP27 activation was dependent on the PKC/P38 pathway, and led downstream to activation of the PI3K/AKT pathway. Other PRAs induced similar cholestatic effects while non PRAs were ineffective. Our results demonstrate that PRAs can induce cholestatic features in human hepatocytes through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways and consequently support the conclusion that in clinic they can cause a non-immune-mediated cholestasis that is not restricted to patients possessing certain genetic determinants.
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