Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse

Coen, Muireann; Ruepp, Stefan; Lindon, John C.; Nicholson, Jeremy K.; Philippe, François; Lenz, Eva M.; Wilson, Ian D.

doi:10.1016/j.jpba.2003.12.019

Cited by 159 publications

(86 citation statements)

References 32 publications

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“…Coen et al 75 retrieved gene expression data and performed different types of NMR experiments of liver tissue from rats dosed with acetaminophen. The design study included 70 rats, 5 time points, and 4 different dose levels.…”

Section: Dynamic Studiesmentioning

confidence: 99%

Chemometrics in Metabonomics

2006

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We provide an overview of how the underlying philosophy of chemometrics is integrated throughout metabonomic studies. Four steps are demonstrated: (1) definition of the aim, (2) selection of objects, (3) sample preparation and characterization, and (4) evaluation of the collected data. This includes the tools applied for linear modeling, for example, Statistical Experimental Design (SED), Principal Component Analysis (PCA), Partial least-squares (PLS), Orthogonal-PLS (OPLS), and dynamic extensions thereof. This is illustrated by examples from the literature.

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Section: Dynamic Studiesmentioning

confidence: 99%

Chemometrics in Metabonomics

2006

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“…The ␥-glutamyl-cysteine synthetase (Gsh1) 1 is considered as the ratelimiting enzyme of the GSH pathway since the homologous mammalian enzyme is inhibited in vitro by high levels of GSH (9), the end product of the pathway. Accordingly, previous work supports this notion in yeast (10), but no definitive proof has been provided, and this question remains opened.Generally, studies based on proteomic and gene expression profiling are interpreted in terms of cell metabolism, assuming a trivial link between protein expression and metabolic states, but few combined transcriptome, proteome, and metabolome studies (2,(11)(12)(13)(14) have been made to experimentally test these assumptions. The present study is intended to address the question of the correlation of metabolic data with the wealth of proteomic, genomic, and regulatory data currently available on one of the best investigated metabolic pathways.…”

mentioning

confidence: 99%

Combined Proteome and Metabolite-profiling Analyses Reveal Surprising Insights into Yeast Sulfur Metabolism

Lafaye

Junot

Pereira

et al. 2005

Journal of Biological Chemistry

121

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Metabolomics is considered as an emerging new tool for functional proteomics in the identification of new protein function or in projects aiming at modeling whole cell metabolism. When combined with proteome studies, metabolite-profiling analyses revealed unanticipated insights into the yeast sulfur pathway. In response to cadmium, the observed overproduction of glutathione, essential for the detoxification of the metal, can be entirely accounted for by a marked drop in sulfur-containing protein synthesis and a redirection of sulfur metabolite fluxes to the glutathione pathway. A kinetic analysis showed sequential and dramatic changes in intermediate sulfur metabolite pools within the first hours of the treatment. Strikingly, whereas proteome and metabolic data were positively correlated under cadmium conditions, proteome and metabolic data were negatively correlated during other growth conditions, i.e. methionine supplementation or sulfate starvation. These differences can be explained by alternative mechanisms in the regulation of Met4, the activator of the sulfur pathway. Whereas Met4 activity is controlled by the cellular cysteine content in response to sulfur source and availability, the present study suggests that Met4 activation under cadmium conditions is cysteine-independent. The results clearly indicate that the metabolic state of a cell cannot be safely predicted based solely on proteomic and/or gene expression data. Combined metabolome and proteome studies are necessary to draw a comprehensive and integrated view of cell metabolism.Assimilable sulfur is essential for all living organisms. The cell requirement for sulfur can be fulfilled by the uptake of sulfur-containing amino acids or by assimilation of inorganic sulfur into organic compounds such as cysteine or homocysteine (1, 2). In yeast, homocysteine is the precursor of methionine through the methyl cycle and of cysteine through the transsulfuration pathway ( Fig. 1) (3). Cysteine is the sensor of the metabolic state in the sulfur amino acid pathway (4) and is required for the synthesis of GSH, an essential antioxidant molecule also important for detoxification.The yeast sulfur pathway has been extensively investigated at the genetic, enzymatic, and regulatory levels (3). The pools of most metabolites of the pathway have been analyzed (5, 6), and the K m values of many enzymes have been measured (3). However, some metabolic data such as the metabolite fluxes in the pathway and the concentration of the metabolites of the transsulfuration pathway (homocysteine and cystathionine) are lacking. Moreover, the levels of some sulfur metabolites are presumed to be modified in different mutants and under different physiological conditions (i.e. sulfur starvation, the presence of a sulfur metabolite, or a toxic metal in the medium), but the few quantitative data that are available are restricted to a small part of the pathway (5). Thus, it has been shown that cadmium (Cd 2ϩ ) strongly increases GSH synthesis (7), which is consistent with the primary impor...

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“…Recently, transcriptomic and proteomic technologies [9][10][11][12][13] have been successfully utilized to reveal that APAP can cause noteworthy changes in gene expression and protein modifications that alter function. These genes and proteins play important roles in pathways related to oxidative stress, mitochondrial function and mitochondrial structure as well as signaling pathways and hepatic necrosis.…”

Section: Introductionmentioning

confidence: 99%

“…These genes and proteins play important roles in pathways related to oxidative stress, mitochondrial function and mitochondrial structure as well as signaling pathways and hepatic necrosis. The metabolomics profiles, which primarily represent downstream changes in transcription and proteomic changes, have been adopted to investigate the mechanism of APAP-induced toxicity and to discover novel biomarkers of hepatotoxicity [12][13][14][15][16][17]. In previous studies, NMR spectroscopy and ultra performance liquid chromatography/mass spectrometry (UPLC/MS)-based metabolomics were employed to study urinary metabolic perturbations induced by APAP administration [15] and the drug's metabolites profile [14].…”

Section: Introductionmentioning

confidence: 99%

“…These results showed the depletion of antioxidants (e.g., ferulic acid), trigonelline, S-adenosyl-methionine (SAMe), and energy-related metabolites caused by APAP administration. In other studies [12,13], NMR-based metabolomics and transcriptomics have been employed to investigate metabolic changes in intact liver tissue, tissue extracts and plasma from mice dosed with APAP. Results indicated that APAP can disrupt energy metabolism including glycolysis and lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Systems Biology Investigation to Discover Metabolic Biomarkers of Acetaminophen-Induced Hepatic Injury Using Integrated Transcriptomics and Metabolomics

2013

J Mol Biomark Diagn

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Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse

Cited by 159 publications

References 32 publications

Chemometrics in Metabonomics

Chemometrics in Metabonomics

Combined Proteome and Metabolite-profiling Analyses Reveal Surprising Insights into Yeast Sulfur Metabolism

Systems Biology Investigation to Discover Metabolic Biomarkers of Acetaminophen-Induced Hepatic Injury Using Integrated Transcriptomics and Metabolomics

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