{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:23:50Z","timestamp":1790832230962,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:00:00Z","timestamp":1604448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Clinical and Translational Science Award","award":["5UL1 RR024975-03"],"award-info":[{"award-number":["5UL1 RR024975-03"]}]},{"name":"NIH\/NCRR","award":["G20 RR030956"],"award-info":[{"award-number":["G20 RR030956"]}]},{"name":"Vanderbilt Ingram Cancer Center","award":["P30 CA68485"],"award-info":[{"award-number":["P30 CA68485"]}]},{"name":"Vanderbilt Vision Center","award":["P30 EY08126"],"award-info":[{"award-number":["P30 EY08126"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g\/kg), bromobenzene (0.4 g\/kg), and carbon tetrachloride (0.3 g\/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.<\/jats:p>","DOI":"10.3390\/ijms21218250","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T10:29:00Z","timestamp":1604485740000},"page":"8250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3368-2496","authenticated-orcid":false,"given":"Venkat R.","family":"Pannala","sequence":"first","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanea K.","family":"Estes","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8407-5621","authenticated-orcid":false,"given":"Mohsin","family":"Rahim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Trenary","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy P.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiyo","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Printz","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaques","family":"Reifman","sequence":"additional","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamey D.","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"},{"name":"Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9775-7469","authenticated-orcid":false,"given":"Anders","family":"Wallqvist","sequence":"additional","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.4254\/wjh.v9.i16.715","article-title":"Non-alcoholic fatty liver disease: An expanded review","volume":"9","author":"Benedict","year":"2017","journal-title":"World J. 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