Title
Toxicogenomics of bromobenzene hepatotoxicity: A combined transcriptomics and proteomics approach
Author
Heijne, W.H.M.
Stierum, R.H.
Slijper, M.
van Bladeren, P.J.
van Ommen, B.
Publication year
2003
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.
Subject
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
To reference this document use:
http://resolver.tudelft.nl/uuid:58c65a7f-22a4-446c-9976-6ce8cc322b46
DOI
https://doi.org/10.1016/s0006-2952(02)01613-1
TNO identifier
236981
ISSN
0006-2952
Source
Biochemical Pharmacology, 65 (5), 857-875
Document type
article