K Ashby1, E E Navarro Almario2, W Tong1, J Borlak3, R Mehta4, M Chen1. 1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA. 2. Office of Computational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. 3. Hannover Medical School, Center of Pharmacology and Toxicology, Hannover, Germany. 4. Division of Gastroenterology and Inborn Error Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Abstract
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.
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 acidshepatotoxicity 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 acidtoxicity. 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 acidhepatotoxicity. CONCLUSION: Species differences should be considered in the development of bile acid related therapeutics. Although the mechanism of bile acidhepatotoxicity is still not fully understood, continued mechanistic studies will deepen our understanding.