title: Analysis of time-related metabolic fluctuations induced by ethionine in the rat.
abstract: The time-course of metabolic events following response to a model hepatotoxin ethionine (800 mg/kg) was investigated over a 7 day period in rats using high-resolution (1)H NMR spectroscopic analysis of urine and multivariate statistics. Complementary information was obtained by multivariate analysis of (1)H MAS NMR spectra of intact liver and by conventional histopathology and clinical chemistry of blood plasma. (1)H MAS NMR spectra of liver showed toxin-induced lipidosis 24 h postdose consistent with the steatosis observed by histopathology, while hypertaurinuria was suggestive of liver injury. Early biochemical changes in urine included elevation of guanidinoacetate, suggesting impaired methylation reactions. Urinary increases in 5-oxoproline and glycine suggested disruption of the gamma-glutamyl cycle. Signs of ATP depletion together with impairment of the energy metabolism were given from the decreased levels in tricarboxylic acid cycle intermediates, the appearance of ketone bodies in urine, the depletion of hepatic glucose and glycogen, and also hypoglycemia. The observed increase in nicotinuric acid in urine could be an indication of an increase in NAD catabolism, a possible consequence of ATP depletion. Effects on the gut microbiota were suggested by the observed urinary reductions in the microbial metabolites 3-/4-hydroxyphenyl propionic acid, dimethylamine, and tryptamine. At later stages of toxicity, there was evidence of kidney damage, as indicated by the tubular damage observed by histopathology, supported by increased urinary excretion of lactic acid, amino acids, and glucose. These studies have given new insights into mechanisms of ethionine-induced toxicity and show the value of multisystem level data integration in the understanding of experimental models of toxicity or disease.
authors.affiliation: Biomolecular Medicine, Imperial College London, Sir Alexander Fleming Building, Imperial College Road, South Kensington, London, SW7 2AZ, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Skordi
authors.forename: Ivan K S
authors.initials: IK
authors.lastname: Yap
authors.forename: Sandrine P
authors.initials: SP
authors.lastname: Claus
authors.forename: François-Pierre J
authors.initials: FP
authors.lastname: Martin
authors.forename: Olivier
authors.initials: O
authors.lastname: Cloarec
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D004734:Energy Metabolism / Q000187:drug effects; D005001:Ethionine / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives / Q000652:urine; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D000963:Antimetabolites; C004946:glycocyamine; D005998:Glycine; D005001:Ethionine