Evaluation of carbon tetrachloride-induced stress on rat hepatocytes by 31P NMR and MALDI-TOF mass spectrometry: lysophosphatidylcholine generation from unsaturated phosphatidylcholines

Bauer, Alexander; Schumann, Anika; Gilbert, Matthias; Wilhelm, Christian; Hengstler, Jan G.; Schiller, Jürgen; Fuchs, Beate

doi:10.1016/j.chemphyslip.2009.02.006

Cited by 17 publications

(8 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An example of an unexpected result in the Open TG-GATEs dataset is the expression response induced by carbon tetrachloride in cultivated human hepatocytes which caused only very few gene expression alterations, although carbon tetrachloride is known to represent a strong hepatotoxic compound (Hoehme et al 2007(Hoehme et al , 2010). An experimental explanation may be that it is technically challenging to suspend the highly lipophilic carbon tetrachloride in a way that all cultivated cells are exposed homogeneously (Bauer et al 2009). This unexpected subset of data was identified by a tool developed in this study, the 'progression profile error indicator,' which identifies non-monotonous concentration progression of deregulated genes.…”

Section: Limitations and Technical Aspectsmentioning

confidence: 99%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

Self Cite

View full text Add to dashboard Cite

A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically infl...

show abstract

Section: Limitations and Technical Aspectsmentioning

confidence: 99%

Toxicogenomics directory of chemically exposed human hepatocytes

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…On one hand, carnitine deficiency observed in our study might indicate that energy metabolism was disturbed by partial hepatectomy in the HCC patients becasue carnitine has functioned to reduce the availability of lipid peroxidation by transporting fatty acids into the mitochondria for beta-oxidation to generate adenosine triphosphate (ATP) energy. On the other hand, the increase of serum carnitine could be considered a new index of improved liver function [27], suggesting that L-carnitine could inhibit hepatocarcinogenesis via protection of mitochondia in another investigation [28]. Taken together, sharp down-regulation of carnitine implied that reduced energy production may occur in 3 to 5 months after partial hepatectomy.…”

Section: Multivariate Analysis and Annotation Of Metabolic Shiftsmentioning

confidence: 96%

Metabolomics Analysis of the Responses to Partial Hepatectomy in Hepatocellular Carcinoma Patients

Chan¹,

Lin²,

Sun³

et al. 2011

AJAC

View full text Add to dashboard Cite

In this study, liquid chromatography/quadrupole time of flight mass spectrometry (LC/QTOFMS) was employed for investigating the metabolome of the sera collected from hepatocellular carcinoma (HCC) patients before and 3 to 5 months after partial hepatectomy. To investigate the changes in metabolic phenotypes after the hepatic resection, principal components analysis (PCA) and support vector machine (SVM) were performed for the data grouping and classification. Based on the obtained SVM model, mass spectrometry spectra, database searching as well as the confirmation from authentic standards, several differentiating metabolites were tentatively identified. To improve visualization, z-score plot and heat map display were performed, which exhibited the changes in concentration of the metabolites. As a result, depletion of circulating carnitine, reduced amino acid biosynthesis and increased rate of lipid peroxidation were observed. Meanwhile, up-regulation of hypoxanthine indicated that purine metabolism might serve as the salvage pathway. Collectively, the results reflected metabolic responses to surgical operation in HCC patients, suggesting perturbation of energy metabolism may occur in 3 to 5 months after the partial hepatectomy.

show abstract

“…Moreover, the nonapeptide antibiotic leucinostatin A acts as an ionophore. 99 In addition, a multitude of other antibiotics 91 or alkaloids, 100 polar organic compounds such as paraquat, 101,102 and also nonpolar compounds such as polycyclic aromatic hydrocarbons, 103 some solvents, such as carbon tetrachloride, 104 and detergents, 105,106 as well as inorganic compounds such as salts of heavy metal ions such as Hg 2 Cl 2 107 or quartz dust, 108 even excercise, 109 or heat stress, 110 induce activation of enzymes.…”

Section: Is the Generation Of Radicals Caused By An Alteration Of Thementioning

confidence: 99%

Is Lipid Peroxidation of Polyunsaturated Acids the Only Source of Free Radicals That Induce Aging and Age-Related Diseases?

Spiteller

2010

Rejuvenation Research

View full text Add to dashboard Cite

The increase in free radicals is hypothesised to cause aging and age-related diseases. The most common source of free radicals is thought to be superoxide. This superoxide is claimed to be released from mitochondria during the enzymatic transformation of oxygen to water by a "leakage" process. This article presents evidence that leakage does not occur. Instead, protonated superoxide radicals are generated by lipid peroxidation processes. In nature, polyunsaturated fatty acids (PUFAs) represent particularly oxygen-sensitive compounds. Apparently, nature uses this sensitivity for signalling processes by producing lipidhydroperoxides (LOOHs) by any change to cell membrane structure. LOOHs easily undergo further enzymatic transformations to compounds which contribute to activation of genes. Bivalent metal ions within the active site of lipoxygenases catalyse LOOH production. The metal ions generate radicals which are transformed within the enzyme complex to non-radical molecules. Thus radicals never leave the enzyme complex except in severe stress situations. In this case the radical intermediates attack bonds, keeping the metal ion in its complex state. Thus, metal ions are released and react in a Fenton reaction with LOOH molecules produced earlier by lipoxygenase to form LO. radicals. Radicals are typically four orders of magnitude more reactive than non-radical molecules. Their action is not under genetic control, they attack nearly all biological molecules, destroying lipids, proteins, nucleic acids, hormones and enzymes until the radicals are quenched by scavenger molecules. The principal degradation routes are outlined in this review. Lysophospholipids are generated in large amounts after stress by activation of phospholipases and are transformed to LO. radicals. These can abstract a hydrogen radical from a lysophospholipid. The radical thus formed adds oxygen and decomposes to a 2-oxolysophospholipid and a HOO. radical (protonated superoxide). HOO. radicals in turn abstract hydrogen atoms from other molecules and produce H(2)O(2). Since any cell preparation method causes membrane destruction, it is inevitable that protonated superoxide is generated, explaining why H(2)O(2) molecules are found as "byproducts" of many reactions.

show abstract

Evaluation of carbon tetrachloride-induced stress on rat hepatocytes by 31P NMR and MALDI-TOF mass spectrometry: lysophosphatidylcholine generation from unsaturated phosphatidylcholines

Cited by 17 publications

References 48 publications

Toxicogenomics directory of chemically exposed human hepatocytes

Toxicogenomics directory of chemically exposed human hepatocytes

Metabolomics Analysis of the Responses to Partial Hepatectomy in Hepatocellular Carcinoma Patients

Is Lipid Peroxidation of Polyunsaturated Acids the Only Source of Free Radicals That Induce Aging and Age-Related Diseases?

Contact Info

Product

Resources

About