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.
Highlights
Different classes of marketed drugs and herbals have been reported to cause drug-induced liver injury (DILI) in humans, accounting for more than 50% of cases of acute liver failure in the United States[1]
Activation of p38 mitogen-activated protein kinase (MAPK) results in the downstream phosphorylation of HSP27 that can bind to AKT and acts as a scaffold protein to permit phosphorylation of AKT by phosphoinositide 3-kinase (PI3K) in order to protect against cell death by blocking apoptosis
Age, high daily doses and human leukocyte antigen (HLA)-B*57:01 allele have been shown to be associated with higher risk of liver injury due to FLX
Summary
Different classes of marketed drugs and herbals have been reported to cause drug-induced liver injury (DILI) in humans, accounting for more than 50% of cases of acute liver failure in the United States[1]. FLX is the most common reason of idiosyncratic liver injury in Sweden, with 16% of all DILI cases and the second most common cause of drug-induced cholestasis in the United Kingdom[11, 12]. Mechanisms underlying FLX-induced hepatocellular injury and cholestasis remain non-elucidated. It is assumed that occurrence of liver injury in patients under FLX treatment is caused by immune-mediated response and favored by genetic determinants[9, 13]. Activation of p38 MAPK results in the downstream phosphorylation of HSP27 that can bind to AKT and acts as a scaffold protein to permit phosphorylation of AKT by phosphoinositide 3-kinase (PI3K) in order to protect against cell death by blocking apoptosis.
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