Document Detail


Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats.
MedLine Citation:
PMID:  23360887     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 1,900 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.
Authors:
Makoto Yamazaki; Manami Miyake; Hiroko Sato; Naoya Masutomi; Naohisa Tsutsui; Klaus-Peter Adam; Danny C Alexander; Kay A Lawton; Michael V Milburn; John A Ryals; Jacob E Wulff; Lining Guo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-26
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  -     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818, Japan.
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