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Title: Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.

Authors: Kyriakides, Michael; Hardwick, Rhiannon N; Jin, Zhaosheng; Goedken, Michael J; Holmes, Elaine; Cherrington, Nathan J; Coen, Muireann

Published In Toxicol Sci, (2014 Nov)

Abstract: Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.

PubMed ID: 25145655 Exiting the NIEHS site

MeSH Terms: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug-Induced Liver Injury/etiology; Drug-Induced Liver Injury/metabolism*; Drug-Induced Liver Injury/urine; Drug-Related Side Effects and Adverse Reactions/etiology; Drug-Related Side Effects and Adverse Reactions/metabolism*; Drug-Related Side Effects and Adverse Reactions/urine; Energy Metabolism/drug effects; Folic Acid/metabolism; Folic Acid/urine; Liver/drug effects; Liver/metabolism*; Liver/pathology; Magnetic Resonance Spectroscopy; Male; Metabolomics; Methotrexate/administration & dosage; Methotrexate/pharmacokinetics; Methotrexate/toxicity*; Methotrexate/urine; Non-alcoholic Fatty Liver Disease/complications; Non-alcoholic Fatty Liver Disease/metabolism*; Oxidative Stress/drug effects; Rats, Sprague-Dawley; Tissue Distribution

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