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Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis

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Author: Heijne, W.H.M. · Lamers, R.J.A.N. · Bladeren, P.J. van · Groten, J.P. · Nesselrooij, J.H.J. van · Ommen, B. van
Institution: TNO Kwaliteit van Leven
Source:Toxicologic Pathology, 4, 33, 425-433
Identifier: 238610
doi: doi:10.1080/01926230590958146
Keywords: Biology · Physiological Sciences · Bromobenzene · Centrilobular necrosis · Hepatotoxicity · Metabolite profiling · Metabolomics · Toxicogenomics · Transcriptomics · alanine · asialoglycoprotein receptor · beta actin · bromobenzene · casein kinase II · creatine · creatinine · cyclin G1 · cycline · dimethylglycine · ferritin · fibrinogen · fructose bisphosphate aldolase · glyceraldehyde 3 phosphate dehydrogenase · lactic acid · methionine · nucleophosmin · orosomucoid · peroxiredoxin · phosphatidylcholine sterol acyltransferase · phosphoglycerate mutase · phospholipid · protein bcl 2 · protein p21 · protein p53 · taurine · tissue inhibitor of metalloproteinase 1 · tubulin · tyrosine · unindexed drug · amino acid metabolism · animal model · apoptosis · article · blood level · controlled study · DNA microarray · dose response · gene · gene expression · gene sequence · glycolysis · liver necrosis · liver toxicity · male · metabolomics · nonhuman · nuclear magnetic resonance spectroscopy · nucleotide sequence · priority journal · rat · transcriptomics · urine level · Amino Acids · Animals · Bromobenzenes · Dose-Response Relationship, Drug · Gene Expression Profiling · Hepatitis, Toxic · Liver · Male · Necrosis · Principal Component Analysis · Rats · Rats, Wistar · Transcription, Genetic


This study investigated whether integrated analysis of transcriptomics and metabolomics data increased the sensitivity of detection and provided new insight in the mechanisms of hepatotoxicity. Metabolite levels in plasma or urine were analyzed in relation to changes in hepatic gene expression in rats that received bromobenzene to induce acute hepatic centrilobular necrosis. Bromobenzene-induced lesions were only observed after treatment with the highest of 3 dose levels. Multivariate statistical analysis showed that metabolite profiles of blood plasma were largely different from controls when the rats were treated with bromobenzene, also at doses that did not elicit histopathological changes. Changes in levels of genes and metabolites were related to the degree of necrosis, providing putative novel markers of hepatotoxicity. Levels of endogenous metabolites like alanine, lactate, tyrosine and dimethylglycine differed in plasma from treated and control rats. The metabolite profiles of urine were found to be reflective of the exposure levels. This integrated analysis of hepatic transcriptomics and plasma metabolomics was able to more sensitively detect changes related to hepatotoxicity and discover novel markers. The relation between gene expression and metabolite levels was explored and additional insight in the role of various biological pathways in bromobenzene-induced hepatic necrosis was obtained, including the involvement of apoptosis and changes in glycolysis and amino acid metabolism. The complete Table 2 is available as a supplemental file online at To access the file, click on the issue link for 33(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through Copyright © by the Society of Toxicologic Pathology.