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.

• Authors: Muireann Coen, Elizabeth J Want, T Andrew Clayton, Cynthia M Rhode, Young Shick Hong, Hector C Keun, Glenn H Cantor, Alan L Metz, Donald G Robertson, Michael D Reily, Elaine Holmes, John C Lindon, Jeremy K Nicholson
• Journal: Journal of proteome research (J Proteome Res) Vol. 8 Issue 11 Pg. 5175-87 (Nov 2009) ISSN: 1535-3907 [Electronic] United States
• PMID: 19821561 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Galactosamine

Topics

• Animals
• Biomarkers (chemistry, metabolism)
• Chemical and Drug Induced Liver Injury (metabolism, pathology)
• Feces (chemistry)
• Galactosamine (metabolism, toxicity)
• Humans
• Liver (chemistry, metabolism, pathology)
• Male
• Molecular Structure
• Nuclear Magnetic Resonance, Biomolecular
• Phenotype
• Rats
• Rats, Sprague-Dawley
• Urine (chemistry)