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Title: Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

Abstract

Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effectsmore » by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the liver's ability to uptake bile acid from the circulation. ► Oxidative stress induced by the toxins altered bile acid biosynthesis in the liver. ► Selected bile acids in the plasma and urine could be sensitive DILI biomarkers.« less

Authors:
; ; ; ;  [1]; ; ; ; ; ;  [2];  [2]
  1. Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan)
  2. Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)
Publication Date:
OSTI Identifier:
22285261
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 268; Journal Issue: 1; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; ALKALINE PHOSPHATASE; BILE ACIDS; BILIRUBIN; BIOLOGICAL MARKERS; CARBON TETRACHLORIDE; CYCLOSPORINE; ETHIONINE; INJURIES; LIVER; LIVER CELLS; NECROSIS; PATHOGENESIS; RATS; TETRACYCLINES; TOXINS; URINE

Citation Formats

Yamazaki, Makoto, Miyake, Manami, Sato, Hiroko, Masutomi, Naoya, Tsutsui, Naohisa, Adam, Klaus-Peter, Alexander, Danny C., Lawton, Kay A., Milburn, Michael V., Ryals, John A., Wulff, Jacob E., and Guo, Lining, E-mail: lguo@metabolon.com. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.01.018.
Yamazaki, Makoto, Miyake, Manami, Sato, Hiroko, Masutomi, Naoya, Tsutsui, Naohisa, Adam, Klaus-Peter, Alexander, Danny C., Lawton, Kay A., Milburn, Michael V., Ryals, John A., Wulff, Jacob E., & Guo, Lining, E-mail: lguo@metabolon.com. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats. United States. doi:10.1016/J.TAAP.2013.01.018.
Yamazaki, Makoto, Miyake, Manami, Sato, Hiroko, Masutomi, Naoya, Tsutsui, Naohisa, Adam, Klaus-Peter, Alexander, Danny C., Lawton, Kay A., Milburn, Michael V., Ryals, John A., Wulff, Jacob E., and Guo, Lining, E-mail: lguo@metabolon.com. Mon . "Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats". United States. doi:10.1016/J.TAAP.2013.01.018.
@article{osti_22285261,
title = {Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats},
author = {Yamazaki, Makoto and Miyake, Manami and Sato, Hiroko and Masutomi, Naoya and Tsutsui, Naohisa and Adam, Klaus-Peter and Alexander, Danny C. and Lawton, Kay A. and Milburn, Michael V. and Ryals, John A. and Wulff, Jacob E. and Guo, Lining, E-mail: lguo@metabolon.com},
abstractNote = {Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the liver's ability to uptake bile acid from the circulation. ► Oxidative stress induced by the toxins altered bile acid biosynthesis in the liver. ► Selected bile acids in the plasma and urine could be sensitive DILI biomarkers.},
doi = {10.1016/J.TAAP.2013.01.018},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 268,
place = {United States},
year = {Mon Apr 01 00:00:00 EDT 2013},
month = {Mon Apr 01 00:00:00 EDT 2013}
}