title: Comparative metabonomics of differential hydrazine toxicity in the rat and mouse.
abstract: Interspecies variation between rats and mice has been studied for hydrazine toxicity using a novel metabonomics approach. Hydrazine hydrochloride was administered to male Sprague-Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. Urine samples were collected at sequential time points up to 168 h post dose and analyzed by 1H NMR spectroscopy. The metabolites of hydrazine, namely diacetyl hydrazine and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid (THOPC), were detected in both the rat and mouse urine samples. Monoacetyl hydrazine was detected only in urine samples from the rat and its absence in the urine of the mouse was attributed to a higher activity of N-acetyl transferases in the mouse compared with the rat. Differential metabolic effects observed between the two species included elevated urinary beta-alanine, 3-D-hydroxybutyrate, citrulline, N-acetylcitrulline, and reduced trimethylamine-N-oxide excretion unique to the rat. Metabolic principal component (PC) trajectories highlighted the greater degree of toxic response in the rat. A data scaling method, scaled to maximum aligned and reduced trajectories (SMART) analysis, was used to remove the differences between the metabolic starting positions of the rat and mouse and varying magnitudes of effect, to facilitate comparison of the response geometries between the rat and mouse. Mice followed "biphasic" open PC trajectories, with incomplete recovery 7 days after dosing, whereas rats followed closed "hairpin" time profiles, indicating functional reversibility. The greater magnitude of metabolic effects observed in the rat was supported by the more pronounced effect on liver pathology in the rat when compared with the mouse.
authors.affiliation: Biological Chemistry, Biomedical Sciences Division, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, UK. mary.bollard@imperial.ac.uk
authors.forename: Mary E
authors.initials: ME
authors.lastname: Bollard
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.forename: Olaf
authors.initials: O
authors.lastname: Beckonert
authors.forename: Tim M D
authors.initials: TM
authors.lastname: Ebbels
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Nicholls
authors.forename: John P
authors.initials: JP
authors.lastname: Shockcor
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.forename: Greg
authors.initials: G
authors.lastname: Stevens
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002853:Chromatography, Liquid / Q000379:methods; D006834:Hydrazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008107:Liver Diseases / Q000453:epidemiology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors; D023382:Toxicity Tests, Acute / Q000379:methods; D014556:Urine / Q000737:chemistry
chemical_list: D006834:Hydrazines; C029424:hydrazine