Mechanistic Insights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells

被引:14
作者
Burbank, Matthew Gibson [1 ,2 ,3 ]
Sharanek, Ahmad [1 ,2 ]
Burban, Audrey [1 ,2 ]
Mialanne, Herve [3 ]
Aerts, Helene [3 ]
Guguen-Guillouzo, Christiane [1 ,2 ]
Weaver, Richard John [4 ]
Guillouzo, Andre [1 ,2 ]
机构
[1] INSERM, UMR Foie Metab & Canc 991, Rennes, France
[2] Univ Rennes 1, Rennes, France
[3] Biol Servier, F-45520 Gidy, France
[4] Inst Rech Int Servier, F-92150 Suresnes, France
关键词
endothelin receptor antagonists; cholestasis; hepatotoxicity; bile canaliculi; HepaRG cells; PULMONARY ARTERIAL-HYPERTENSION; SALT EXPORT PUMP; CULTURED HUMAN HEPATOCYTES; BILE CANALICULI DYNAMICS; CHAIN KINASE PATHWAY; INDUCED LIVER-INJURY; HEPATOBILIARY TRANSPORTERS; CYCLOSPORINE-A; UP-REGULATION; MACITENTAN;
D O I
10.1093/toxsci/kfx062
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Several endothelin receptor antagonists (ERAs) have been developed for the treatment of pulmonary arterial hypertension (PAH). Some of them have been related to clinical cases of hepatocellular injury (sitaxentan [SIT]) and/or cholestasis (bosentan [BOS]). We aimed to determine if ambrisentan (AMB) and macitentan (MAC), in addition to BOS and SIT, could potentially cause liver damage in man by use of human HepaRG cells. Our results showed that like BOS, MAC-induced cytotoxicity and cholestatic disorders characterized by bile canaliculi dilatation and impairment of myosin light chain kinase signaling. Macitentan also strongly inhibited taurocholic acid and carboxy-2', 7'-dichlorofluorescein efflux while it had a much lower inhibitory effect on influx activity compared to BOS and SIT. Moreover, these three drugs caused decreased intracellular accumulation and parallel increased levels of total bile acids (BAs) in serum-free culture media. In addition, all drugs except AMB variably deregulated gene expression of BA transporters. In contrast, SIT was hepatotoxic without causing cholestatic damage, likely via the formation of reactive metabolites and AMB was not hepatotoxic. Together, our results show that some ERAs can be hepatotoxic and that the recently marketed MAC, structurally similar to BOS, can also cause cholestatic alterations in HepaRG cells. The absence of currently known or suspected cases of cholestasis in patients suffering from PAH treated with MAC is rationalized by the lower therapeutic doses and C-max, and longer receptor residence time compared to BOS.
引用
收藏
页码:451 / 464
页数:14
相关论文
共 62 条
[1]   Pharmacokinetic-Pharmacodynamic Relationships of Macitentan, a New Endothelin Receptor Antagonist, After Multiple Dosing in Healthy Korean Subjects [J].
Ahn, Li Young ;
Kim, Sung Eun ;
Yi, SoJeong ;
Dingemanse, Jasper ;
Lim, Kyoung Soo ;
Jang, In-Jin ;
Yu, Kyung-Sang .
AMERICAN JOURNAL OF CARDIOVASCULAR DRUGS, 2014, 14 (05) :377-385
[2]   Differential sensitivity of metabolically competent and non-competent HepaRG cells to apoptosis induced by diclofenac combined or not with TNF-α [J].
Al-Attrache, Houssein ;
Sharanek, Ahmad ;
Burban, Audrey ;
Burbank, Matthew ;
Gicquel, Thomas ;
Abdel-Razzak, Ziad ;
Guguen-Guillouzo, Christiane ;
Morel, Isabelle ;
Guillouzo, Andre .
TOXICOLOGY LETTERS, 2016, 258 :71-86
[3]   Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells [J].
Aninat, C ;
Piton, A ;
Glaise, D ;
Le Charpentier, T ;
Langouët, S ;
Morel, F ;
Guguen-Guillouzo, C ;
Guillouzo, A .
DRUG METABOLISM AND DISPOSITION, 2006, 34 (01) :75-83
[4]   Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells [J].
Antherieu, Sebastien ;
Bachour-El Azzi, Pamela ;
Dumont, Julie ;
Abdel-Razzak, Ziad ;
Guguen-Guillouzo, Christiane ;
Fromenty, Bernard ;
Robin, Marie-Anne ;
Guillouzo, Andre .
HEPATOLOGY, 2013, 57 (04) :1518-1529
[5]   Comparative Localization and Functional Activity of the Main Hepatobiliary Transporters in HepaRG Cells and Primary Human Hepatocytes [J].
Bachour-El Azzi, Pamela ;
Sharanek, Ahmad ;
Burban, Audrey ;
Li, Ruoya ;
Le Guevel, Remy ;
Abdel-Razzak, Ziad ;
Stieger, Bruno ;
Guguen-Guillouzo, Christiane ;
Guillouzo, Andre .
TOXICOLOGICAL SCIENCES, 2015, 145 (01) :157-168
[6]  
Barst RJ, 2007, VASC HEALTH RISK MAN, V3, P11
[7]   Long-Term Hepatic Safety of Ambrisentan in Patients With Pulmonary Arterial Hypertension [J].
Ben-Yehuda, Ori ;
Pizzuti, David ;
Brown, Andrea ;
Littman, Marcus ;
Gillies, Hunter ;
Henig, Noreen ;
Peschel, Tobias .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2012, 60 (01) :80-U105
[8]   The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist [J].
Bolli, Martin H. ;
Boss, Christoph ;
Binkert, Christoph ;
Buchmann, Stephan ;
Bur, Daniel ;
Hess, Patrick ;
Iglarz, Marc ;
Meyer, Solange ;
Rein, Josiane ;
Rey, Markus ;
Treiber, Alexander ;
Clozel, Martine ;
Fischli, Walter ;
Weller, Thomas .
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (17) :7849-7861
[9]   Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans [J].
Bruderer, Shirin ;
Hopfgartner, Gerard ;
Seiberling, Michael ;
Wank, Janine ;
Sidharta, Patricia N. ;
Treiber, Alexander ;
Dingemanse, Jasper .
XENOBIOTICA, 2012, 42 (09) :901-910
[10]   Early Alterations of Bile Canaliculi Dynamics and the Rho Kinase/Myosin Light Chain Kinase Pathway Are Characteristics of Drug-Induced Intrahepatic Cholestasis [J].
Burbank, Matthew G. ;
Burban, Audrey ;
Sharanek, Ahmad ;
Weaver, Richard J. ;
Guguen-Guillouzo, Christiane ;
Guillouzo, Andre .
DRUG METABOLISM AND DISPOSITION, 2016, 44 (11) :1780-+