Review article: therapeutic bile acids and the risks for hepatotoxicity

Ashby, K.; Navarro Almario, E. E.; Tong, W.; Borlak, J.; Mehta, R.; Chen, M.

doi:10.1111/apt.14678

Title: Review article: therapeutic bile acids and the risks for hepatotoxicity

Journal Article · Fri Apr 27 00:00:00 EDT 2018 · Alimentary Pharmacology & Therapeutics

DOI:https://doi.org/10.1111/apt.14678· OSTI ID:1434973

Ashby, K. ^[1]; Navarro Almario, E. E. ^[2]; Tong, W. ^[1]; Borlak, J. ^[3]; Mehta, R. ^[4];

^[1]

Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration Jefferson AR USA
Office of Computational Science Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA
Hannover Medical School Center of Pharmacology and Toxicology Hannover Germany
Division of Gastroenterology and Inborn Error Products Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring MD USA

Summary Background Bile acids play important roles in cholesterol metabolism and signal through farnesoid X receptor and G protein‐coupled receptors. Given their importance in liver biology, bile acid therapy enables therapeutic applications beyond the treatment of cholestatic liver disease. However, predicting hepatotoxicity of bile acids in humans is obscured due to inconsistent extrapolations of animal data to humans. Aim To review the evidence that could explain discordant bile acids hepatotoxicity observed in humans and animals. Method Literature search was conducted in PubMed using keywords “bile acid,” “transporter,” “hepatotoxicity,” “clinical study,” “animal study,” “species difference,” “mechanism,” “genetic disorder.” Relevant articles were selected for review. Results Clinically significant hepatotoxicity was reported in response to certain bile acids, namely chenodeoxycholic acid, which was given a boxed warning for potential hepatotoxicity. The chemical structure, specifically the number and orientation of hydroxyl groups, significantly affects their hydrophobicity, an important factor in bile acid toxicity. Experimental studies show that hydrophobic bile acids can lead to liver injury through various mechanisms, such as death receptor signalling, mitochondrial dysfunction and inflammation. Although animal studies play a central role in investigating bile acid safety, there are considerable differences in bile acid composition, metabolism and hepatobiliary disposition across species. This does not allow appropriate safety inference, especially for predicting hepatotoxicity in humans. Exploring evidences stemming from inborn errors, genetic models of disease and toxicology studies further improves an understanding of bile acid hepatotoxicity. Conclusion Species differences should be considered in the development of bile acid related therapeutics. Although the mechanism of bile acid hepatotoxicity is still not fully understood, continued mechanistic studies will deepen our understanding.

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Sponsoring Organization:: USDOE

OSTI ID:: 1434973

Journal Information:: Alimentary Pharmacology & Therapeutics, Journal Name: Alimentary Pharmacology & Therapeutics Vol. 47 Journal Issue: 12; ISSN 0269-2813

Publisher:: Wiley-BlackwellCopyright Statement

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Language:: English

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Simultaneous characterization of bile acids and their sulfate metabolites in mouse liver, plasma, bile, and urine using LC–MS/MS Huang, Jiangeng; Bathena, Sai Praneeth R.; Csanaky, Iván L. Journal of Pharmaceutical and Biomedical Analysis, Vol. 55, Issue 5 https://doi.org/10.1016/j.jpba.2011.03.035	journal	July 2011
Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response Cai, Shi-Ying; Ouyang, Xinshou; Chen, Yonglin JCI Insight, Vol. 2, Issue 5 https://doi.org/10.1172/jci.insight.90780	journal	March 2017
Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J. Toxicology and Applied Pharmacology, Vol. 283, Issue 3 https://doi.org/10.1016/j.taap.2015.01.015	journal	March 2015
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Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT Carlton, Victoria E. H.; Harris, Baruch Z.; Puffenberger, Erik G. Nature Genetics, Vol. 34, Issue 1 https://doi.org/10.1038/ng1147	journal	April 2003
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High-Content Imaging in Human and Rat Hepatocytes Using the Fluorescent Dyes CLF and CMFDA Is Not Specific Enough to Assess BSEP/Bsep and/or MRP2/Mrp2 Inhibition by Cholestatic Drugs Qiu, Luping; Finley, James; Taimi, Mohammed Applied In Vitro Toxicology, Vol. 1, Issue 3 https://doi.org/10.1089/aivt.2015.0014	journal	September 2015
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