title: Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma.
abstract: While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMap(®)Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential.
authors.affiliation: PharmPoint Consulting, 17014 Hersperger Ln, Poolesville, MD 20837, USA.
authors.forename: W
authors.initials: W
authors.lastname: Mattes
authors.affiliation: Toxicologic Pathology Associates, Jefferson, AR, USA.
authors.forename: K
authors.initials: K
authors.lastname: Davis
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Fabian
authors.affiliation: National Center for Toxicological Research, FDA, Jefferson, AR, USA.
authors.forename: J
authors.initials: J
authors.lastname: Greenhaw
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Herold
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Looser
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Mellert
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Groeters
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Marxfeld
authors.affiliation: Metanomics Health GmbH, Berlin, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Moeller
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Montoya-Parra
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Prokoudine
authors.affiliation: BASF SE, Ludwigshafen, Germany. Electronic address: bennard.ravenzwaay@basf.com.
authors.forename: B
authors.initials: B
authors.lastname: van Ravenzwaay
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Strauss
authors.affiliation: Metanomics GmbH, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Walk
authors.affiliation: BASF SE, Ludwigshafen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kamp
mesh_terms: D000818:Animals; D001285:Atropine / Q000633:toxicity; D002216:Captopril / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005485:Flutamide / Q000633:toxicity; D019259:Lamivudine / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008353:Mannitol / Q000633:toxicity; D055432:Metabolomics / Q000379:methods*; D008727:Methotrexate / Q000633:toxicity; D009355:Neomycin / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010672:Phenytoin / Q000633:toxicity; D010879:Piperazines; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013307:Streptomycin / Q000633:toxicity; D014230:Triazoles / Q000633:toxicity; D014635:Valproic Acid / Q000633:toxicity; D014640:Vancomycin / Q000633:toxicity; D015215:Zidovudine / Q000633:toxicity
chemical_list: D010879:Piperazines; D014230:Triazoles; D019259:Lamivudine; D008353:Mannitol; D015215:Zidovudine; C051752:nefazodone; D014635:Valproic Acid; D010672:Phenytoin; D014640:Vancomycin; D011441:Propylthiouracil; D005485:Flutamide; D001285:Atropine; D002216:Captopril; D009355:Neomycin; D013307:Streptomycin; D008727:Methotrexate
keywords: Hepatotoxicity; Metabolomic; Rat plasma