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Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma

Mattes, W., Davis, K., Fabian, E., Greenhaw, J., Herold, M., Looser, R., Mellert, W., Groeters, S., Marxfeld, H., Moeller, N., Montoya-Parra, G., Prokoudine, A., van Ravenzwaay, B., Strauss, V., Walk, T., Kamp, H.·2014·Toxicology Letters
DOI 10.1016/j.toxlet.2014.07.021
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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 i…

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Metadata

Authors
Mattes, W., Davis, K., Fabian, E., Greenhaw, J., Herold, M., Looser, R., Mellert, W., Groeters, S., Marxfeld, H., Moeller, N., Montoya-Parra, G., Prokoudine, A., van Ravenzwaay, B., Strauss, V., Walk, T., & Kamp, H.
Venue
Toxicology Letters
Publisher
Elsevier BV
Published
2014-11
Volume
230
Issue
3
Pages
467-478
ISSN
0378-4274
DOI
10.1016/j.toxlet.2014.07.021
Cited by
65
References
0
Language
en
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