Tight junction stabilization prevents HepaRG cell death in drug-induced intrahepatic cholestasis.

Rie Sonoi,Yoshihisa Hagihara

doi:10.1242/bio.058606

Rie Sonoi, Yoshihisa Hagihara

Open Access

https://doi.org/10.1242/bio.058606

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Abstract

ABSTRACTEntacapone (ENT), a catechol-O-methyltransferase inhibitor, causes liver injury by inducing bile canaliculi (BC) dilation through inhibition of the myosin light kinase pathway. Loss of tight junctions (TJs) induces hepatocyte depolarization, which causes bile secretory failure, leading to liver damage. To understand the influence of TJ structural changes as a consequence of BC dynamics, we compared the datasets of time-lapse and immunofluorescence images for TJ protein ZO-1 in hepatocytes cultured with ENT, forskolin (FOR), ENT/FOR, and those cultured without any drugs. Retrospective analysis revealed that the drastic change in BC behaviors caused TJ disruption and apoptosis in cells cultured with ENT. Exposure to FOR or sodium taurocholate facilitated TJ formation in the cells cultured with ENT and suppressed BC dynamic changes, leading to the inhibition of TJ disruption and apoptosis. Our findings clarify that hepatocyte TJ stabilization protects against cell death induced by BC disruption.

Highlights

Drug-induced liver injuries cause serious adverse events, and intrahepatic cholestasis accounts for approximately 40 % of all drug-induced liver injuries (Lee et al, 2003)
Retrospective analysis revealed that the drastic change in bile canaliculi (BC) behaviors caused tight junction (TJ) disruption and apoptosis in cells cultured with ENT
Exposure to FOR or sodium taurocholate facilitated TJ formation in the cells cultured with ENT and suppressed BC dynamic changes, leading to the inhibition of TJ disruption and apoptosis

Summary

Introduction

Drug-induced liver injuries cause serious adverse events, and intrahepatic cholestasis accounts for approximately 40 % of all drug-induced liver injuries (Lee et al, 2003). Many drugs induce intrahepatic cholestasis, inhibit hepatic transporter functions, and result in hepatotoxicity due to the accumulation of bile acids in the cytosol or in the bile canaliculi (BC) of hepatocytes (Pedersen et al, 2013; Qui et al, 2016). Bile acids induce mitochondrial impairment and the production of reactive oxygen species in hepatocytes (Rodrigues et al, 2018). Some of these drugs do not necessarily inhibit hepatic transporter function (Burbank et al, 2016), and the complicated mechanism underlying intrahepatic cholestasis remains unclear. Entacapone (ENT) is clinically used for the treatment of patients with Parkinson’s syndrome, but is known to evoke liver injury, such as intrahepatic cholestasis (Fisher et al, 2002), in approximately 0.2 % of the patients treated with ENT (Lew et al, 2007; Haasio et al, 2010; Grünig et al, 2017)

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