title: Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.
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.
authors.affiliation: Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyriakides
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.affiliation: Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
authors.forename: Zhaosheng
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
authors.affiliation: Biomolecular Medicine, Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK m.coen@imperial.ac.uk.
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000378:metabolism* / Q000652:urine; D004734:Energy Metabolism / Q000187:drug effects; D005492:Folic Acid / Q000378:metabolism / Q000652:urine; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D005492:Folic Acid; D008727:Methotrexate
keywords: liver toxicity; metabonomics; methionine-choline deficient diet; methotrexate; non-alcoholic steatohepatitis; nuclear magnetic resonance spectroscopy