Mechanistic Aspects and Novel Biomarkers of Responder and Non-Responder Phenotypes in Galactosamine-Induced Hepatitis

The amino sugar galactosamine (gaIN) 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 gaIN 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 gaIN in urine, serum, feces and liver from responders and non-responders. The presence of N-acetylglucosamine and gaIN in the urine correlated with the occurrence and extent of toxic response. Conversely, the novel identification of gaIN-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 gaIN in non-responders. The absence of the UDP-hexosamines in the liver of non-responders further supports differential metabolism of gaIN 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 gaIN This systems level metabonomic approach has provided new mechanistic insights into differential response to gaIN and is widely applicable to the study of interindividual variation in metabolism for any xenobiotic intervention.