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Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity
It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were inc...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Research Network of Computational and Structural Biotechnology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204381/ https://www.ncbi.nlm.nih.gov/pubmed/25379137 http://dx.doi.org/10.1016/j.csbj.2014.08.001 |
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author | Sun, Jinchun Slavov, Svetoslav Schnackenberg, Laura K. Ando, Yosuke Greenhaw, James Yang, Xi Salminen, William Mendrick, Donna L. Beger, Richard |
author_facet | Sun, Jinchun Slavov, Svetoslav Schnackenberg, Laura K. Ando, Yosuke Greenhaw, James Yang, Xi Salminen, William Mendrick, Donna L. Beger, Richard |
author_sort | Sun, Jinchun |
collection | PubMed |
description | It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting. |
format | Online Article Text |
id | pubmed-4204381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Research Network of Computational and Structural Biotechnology |
record_format | MEDLINE/PubMed |
spelling | pubmed-42043812014-11-06 Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity Sun, Jinchun Slavov, Svetoslav Schnackenberg, Laura K. Ando, Yosuke Greenhaw, James Yang, Xi Salminen, William Mendrick, Donna L. Beger, Richard Comput Struct Biotechnol J Article It has been estimated that 10% of acute liver failure is due to “idiosyncratic hepatotoxicity”. The inability to identify such compounds with classical preclinical markers of hepatotoxicity has driven the need to discover a mechanism-based biomarker panel for hepatotoxicity. Seven compounds were included in this study: two overt hepatotoxicants (acetaminophen and carbon tetrachloride), two idiosyncratic hepatotoxicants (felbamate and dantrolene), and three non-hepatotoxicants (meloxicam, penicillin and metformin). Male Sprague–Dawley rats were orally gavaged with a single dose of vehicle, low dose or high dose of the compounds. At 6 h and 24 h post-dosing, blood was collected for metabolomics and clinical chemistry analyses, while organs were collected for histopathology analysis. Forty-one metabolites from previous hepatotoxicity studies were semi-quantified and were used to build models to predict hepatotoxicity. The selected metabolites were involved in various pathways, which have been noted to be linked to the underlying mechanisms of hepatotoxicity. PLS models based on all 41 metabolite or smaller subsets of 6 (6 h), 7 (24 h) and 20 (6 h and 24 h) metabolites resulted in models with an accuracy of at least 97.4% for the hold-out test set and 100% for training sets. When applied to the external test sets, the PLS models predicted that 1 of 9 rats at both 6 h and 24 h treated with idiosyncratic liver toxicants was exposed to a hepatotoxic chemical. In conclusion, the biomarker panel might provide information that along with other endpoint data (e.g., transcriptomics and proteomics) may diagnose acute and idiosyncratic hepatotoxicity in a clinical setting. Research Network of Computational and Structural Biotechnology 2014-08-09 /pmc/articles/PMC4204381/ /pubmed/25379137 http://dx.doi.org/10.1016/j.csbj.2014.08.001 Text en |
spellingShingle | Article Sun, Jinchun Slavov, Svetoslav Schnackenberg, Laura K. Ando, Yosuke Greenhaw, James Yang, Xi Salminen, William Mendrick, Donna L. Beger, Richard Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title | Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title_full | Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title_fullStr | Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title_full_unstemmed | Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title_short | Identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
title_sort | identification of a metabolic biomarker panel in rats for prediction of acute and idiosyncratic hepatotoxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204381/ https://www.ncbi.nlm.nih.gov/pubmed/25379137 http://dx.doi.org/10.1016/j.csbj.2014.08.001 |
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