title: Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide.
abstract: Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferase and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure.
authors.affiliation: Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, USA. maddox@msu.edu
authors.forename: Jane F
authors.initials: JF
authors.lastname: Maddox
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Cosma
authors.forename: Alan P
authors.initials: AP
authors.lastname: Breau
authors.forename: Roy H
authors.initials: RH
authors.lastname: Bible
authors.forename: George G
authors.initials: GG
authors.lastname: Harrigan
authors.forename: Royston
authors.initials: R
authors.lastname: Goodacre
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Glenn H
authors.initials: GH
authors.lastname: Cantor
authors.forename: Gary L
authors.initials: GL
authors.lastname: Cockerell
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D016002:Discriminant Analysis; D006635:Histamine H2 Antagonists / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008111:Liver Function Tests; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D025341:Principal Component Analysis; D011899:Ranitidine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D006635:Histamine H2 Antagonists; D008070:Lipopolysaccharides; D011899:Ranitidine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase