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Toxicogenomics of bromobenzene hepatotoxicity: A combined transcriptomics and proteomics approach

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Author: Heijne, W.H.M. · Stierum, R.H. · Slijper, M. · Bladeren, P.J. van · Ommen, B. van
Type:article
Date:2003
Source:Biochemical Pharmacology, 5, 65, 857-875
Identifier: 236981
doi: doi:10.1016/S0006-2952(02)01613-1
Keywords: Toxicology Health · Physiological Sciences · Bromobenzene · cDNA microarray · Hepatotoxicity · Proteomics · Toxicogenomics · Transcriptomics · alpha glutamylcysteine synthetase · bromobenzene · cathepsin L · enzyme · epoxide hydrolase · glutathione · glutathione transferase · heme oxygenase · messenger RNA · peroxiredoxin · proteasome · unclassified drug · animal experiment · animal model · animal tissue · article · controlled study · enzyme activity · enzyme induction · enzyme regulation · enzyme subunit · gene control · gene expression · gene identification · gene induction · genomics · glutathione metabolism · liver toxicity · lysosome · male · nonhuman · nucleotide sequence · oxidative stress · priority journal · protein content · protein degradation · protein depletion · protein expression · protein synthesis · proteomics · rat · RNA analysis · tissue level · unindexed sequence · weight reduction · Animals · Bromobenzenes · Liver · Male · Oligonucleotide Array Sequence Analysis · Pharmacogenetics · Proteomics · Rats · Rats, Wistar · Transcription, Genetic

Abstract

Toxicogenomics is a novel approach integrating the expression analysis of thousands of genes (transcriptomics) or proteins (proteomics) with classical methods in toxicology. Effects at the molecular level are related to pathophysiological changes of the organisms, enabling detailed comparison of mechanisms and early detection and prediction of toxicity. This report addresses the value of the combined use of transcriptomics and proteomics technologies in toxicology. Acute hepatotoxicity was induced in rats by bromobenzene administration resulting in depleted glutathione levels and reduced average body weights, 24hr after dosage. These physiological symptoms coincided with many changes of hepatic mRNA and protein content. Gene induction confirmed involvement of glutathione-S-transferase isozymes and epoxide hydrolase in bromobenzene metabolism and identified many genes possibly relevant in bromobenzene toxicity. Observed glutathione depletion coincided with induction of the key enzyme in glutathione biosynthesis, γ-glutamylcysteine synthetase. Oxidative stress was apparent from strong upregulation of heme oxygenase, peroxiredoxin 1 and other genes. Bromobenzene-induced protein degradation was suggested from two-dimensional gel electrophoresis, upregulated mRNA levels for proteasome subunits and lysosomal cathepsin L, whereas also genes were upregulated with a role in protein synthesis. Both protein and gene expression profiles from treated rats were clearly distinct from controls as shown by principal component analysis, and several proteins found to significantly change upon bromobenzene treatment were identified by mass spectrometry. A modest overlap in results from proteomics and transcriptomics was found. This work indicates that transcriptomics and proteomics technologies are complementary to each other and provide new possibilities in molecular toxicology. © 2002 Elsevier Science Inc. All rights reserved.