Mechanistic aspects and novel biomarkers of responder and non-responder phenotypes in galactosamine-induced hepatitis.
ABSTRACT The amino sugar galactosamine (galN) induces alterations in the hepatic uridine nucleotide pool and has been widely used as a model of human viral hepatitis. Histopathological and clinical chemistry analyses of a cohort of rats following administration of galN revealed extreme interindividual variability in the extent of the toxic response which enabled classification of 'responder' and 'non-responder' phenotypes. An integrative metabolic profiling approach was applied to characterize biomarkers of exposure to galN in urine, serum, feces and liver from responders and non-responders. The presence of N-acetylglucosamine and galN in the urine correlated with the occurrence and extent of toxic response. Conversely, the novel identification of galN-pyrazines in the feces of non-responders and their virtual absence in the feces of responders suggests an alternative means of distribution and metabolism of galN in non-responders. The absence of the UDP-hexosamines in the liver of non-responders further supports differential metabolism of galN and suggests an ability of non-responders to avoid UDP-glucose depletion. An observed disturbance of gut microbial derived metabolites in the urine and feces of non-responders may suggest a role of the microflora in reducing the effective dose of galN. This systems level metabonomic approach has provided new mechanistic insights into differential response to galN and is widely applicable to the study of interindividual variation in metabolism for any xenobiotic intervention.
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ABSTRACT: Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context.ALTEX. 01/2013; 30(2):209-25.
- ALTEX. 01/2013; 2:209-225.
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ABSTRACT: As with many clinical studies, trials using probiotics have shown clearly that some patients benefit from the treatment while others do not. For example if treatment with probiotics leads to 36% cure rate of diarrhea, why did the other 64% not have the same result? The issue is important for human and indeed experimental animal studies for two main reasons: (i) Would changing the design of the study result in more subjects responding to treatment? (ii) If a subject does not respond what are the mechanistic reasons? In order to tackle the issue of responders and non-responders to therapy, a workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP). The outcome was four recommendations. 1. Clearly define the end goal: this could be supporting a health claim or having the highest clinical effect and impact. 2. Design the study to maximize the chance of a positive response by identifying precise parameters and defining the level of response that will be tested. 3. Base the selection of the intervention on scientific investigations: which strain(s) and/or product formulation should be used and why. 4. Carefully select the study cohort: use biological or genetic markers when available to stratify the patient population before enrollment and decide at what point intervention will provide the best outcome (for example, in acute phase of disease, or during remission, with or without use of pharmaceutical agents). By following these recommendations and selecting an appropriate primary outcome, it is hoped that clinical data will emerge in the future that expands our knowledge of which probiotics benefits which subjects and by what mechanism.Gut Microbes 05/2010; 1(3):200-4.