Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats
| Autor: | Jacob Wulff, Makoto Yamazaki, Kay A. Lawton, Michael V. Milburn, Naoya Masutomi, Naohisa Tsutsui, Danny C. Alexander, Manami Miyake, Hiroko Sato, John A. Ryals, Klaus-Peter Adam, Lining Guo |
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| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Bilirubin Methapyrilene Toxicology Gas Chromatography-Mass Spectrometry Bile Acids and Salts Rats Sprague-Dawley Random Allocation chemistry.chemical_compound Cholestasis Tandem Mass Spectrometry Internal medicine medicine Animals Metabolomics Chromatography High Pressure Liquid Toxins Biological Pharmacology Liver injury Bile acid Chemistry medicine.disease Rats Acetaminophen Oxidative Stress Endocrinology Hepatocytes Chemical and Drug Induced Liver Injury Steatosis Biomarkers TBIL medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 268:79-89 |
| ISSN: | 0041-008X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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