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Profiles of Metabolites and Gene Expression in Rats with Chemically Induced Hepatic Necrosis
1 TNO Nutrition and Food Research, Zeist, The Netherlands Correspondence: Address correspondence to: Wilbert H. M. Heijne, P.O. Box 360, 3700 AJ, Zeist, The Netherlands; e-mail:Heijne{at}pharma.TNO.nl 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 http://taylorandfrancis.metapress.com/openurlasp?genre=journal&issn=0192-6233. 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 www.toxpath.org.
Key Words: Hepatotoxicity • centrilobular necrosis • transcriptomics • metabolite profiling • toxicogenomics • bromobenzene • metabolomics Abbreviations: ALAT, alanine aminotransferase • ALP, Alkaline phosphatase • APR, acute phase response • ASAT, aspartate aminotransferase • BB, bromobenzene • CO, corn oil • G6PD, Glucose-6-phosphate dehydrogenase • G6PT1, Glucose-6-phosphatase, transport protein 1 • GAPDH, glyceraldehyde phosphate dehydrogenase • HO-1, Heme oxygenase 1 • HPD, 4-hydroxyphenylpyruvate dioxygenase • AGT, Alanine-glyoxylate amino-transferase • LDH, lactate dehydrogenase • EPHX1, microsomal epoxide hydrolase • mRNA, messenger RNA • n.s., not statistically significant • NMR, nuclear magnetic resonance spectroscopy • PCA, principal component analysis • TIMP1, tissue inhibitor of metalloproteinase • UT, Untreated
Toxicologic Pathology, Vol. 33, No. 4,
425-433 (2005) |
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