Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways

Scientific Reports
Audrey BurbanChristiane Guguen-Guillouzo

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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Citations

Jan 11, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Audrey BurbanAndré Guillouzo
Sep 21, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ahmad SharanekAndré Guillouzo
Oct 30, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard J Weaver, Jean-Pierre Valentin
Jul 30, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·James C WaddingtonBrian Kevin Park
Apr 12, 2019·Archives of Toxicology·Eva GijbelsMathieu Vinken
Mar 17, 2019·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Ahmad SharanekAndré Guillouzo

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Methods Mentioned

BETA
transfection
protein folding

Software Mentioned

- Capt
GraphPad Prism
ImageJ
Fusion

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