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Cholangiocyte organoids to study drug-induced injury.
Wang, Zhenguo; Xing, Chen; van der Laan, Luc J W; Verstegen, Monique M A; Spee, Bart; Masereeuw, Rosalinde.
Afiliação
  • Wang Z; Division of Pharmacology, Faculty of Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
  • Xing C; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
  • van der Laan LJW; Division of Pharmacology, Faculty of Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
  • Verstegen MMA; Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, The Netherlands.
  • Spee B; Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, The Netherlands.
  • Masereeuw R; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Stem Cell Res Ther ; 15(1): 78, 2024 Mar 13.
Article em En | MEDLINE | ID: mdl-38475870
ABSTRACT

BACKGROUND:

Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood.

METHODS:

Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail.

RESULTS:

CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect.

CONCLUSION:

These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ductos Biliares / Ácidos e Sais Biliares Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ductos Biliares / Ácidos e Sais Biliares Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Holanda