title: Application of in vivo metabolomics to preclinical/toxicological studies: case study on phenytoin-induced systemic toxicity.
abstract: BASF and Metanomics have built-up the database MetaMap(®)-Tox containing rat plasma metabolome data for more than 500 reference compounds. Phenytoin was administered to five Wistar rats of both sexes at dietary dose levels of 600 and 2400 ppm over 28 days and metabolome analysis was performed on days 7, 14 and 28. Clinical pathology did not indicate clear evidence for liver toxicity, whereas liver histopathology revealed slight centrilobular hepatocellular hypertrophy. The metabolome analysis of phenytoin shows metabolome changes at both dose levels and the comparison with MetaMap-Tox indicated strong evidence for liver enzyme induction, as well as liver toxicity. Moreover, evidence for kidney and indirect thyroid effects were observed. This assessment was based on the metabolite changes induced, similarities to specific toxicity patterns and the whole metabolome correlation within MetaMap-Tox. As compared with the classical read-out, a more comprehensive picture of phenytoin's effects is obtained from the metabolome analysis, demonstrating the added value of metabolome data in preclinical/ toxicological studies.
authors.affiliation: BASF SE, Experimental Toxicology & Ecology, Z 470, D-67056 Ludwigshafen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kamp
authors.forename: E
authors.initials: E
authors.lastname: Fabian
authors.forename: S
authors.initials: S
authors.lastname: Groeters
authors.forename: M
authors.initials: M
authors.lastname: Herold
authors.forename: G
authors.initials: G
authors.lastname: Krennrich
authors.forename: R
authors.initials: R
authors.lastname: Looser
authors.forename: W
authors.initials: W
authors.lastname: Mattes
authors.forename: W
authors.initials: W
authors.lastname: Mellert
authors.forename: A
authors.initials: A
authors.lastname: Prokoudine
authors.forename: P
authors.initials: P
authors.lastname: Ruiz-Noppinger
authors.forename: V
authors.initials: V
authors.lastname: Strauss
authors.forename: T
authors.initials: T
authors.lastname: Walk
authors.forename: J
authors.initials: J
authors.lastname: Wiemer
authors.forename: B
authors.initials: B
authors.lastname: van Ravenzwaay
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000097:blood*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D008099:Liver / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods*; D010672:Phenytoin / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D054316:Biomarkers, Pharmacological; D010672:Phenytoin