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.

Dietary l-cysteine inhibits d-galactosamine-induced acute liver injury in rats

“…However, high doses of vitamin A can be toxic, leading to acute liver injury (15). In this study, liver injury was induced by administration of D-GalN, which induces hepatic necrosis in rats (16).…”

“…Because these enzymes are found in hepatocytes, enzymes are released into the bloodstream, leading to abnormally high serum enzyme levels in acute liver damage (24). D-GalN is known to deplete the hepatic uridine nucleotide concentration, which leads to inhibition of protein and mRNA synthesis, causing cell organelle damage and, ultimately, hepatic necrosis (16). Serum AST and ALT activities increased after D-GalN exposure (25), rising over 24 h and remaining high for 4 days after liver injury (24).…”

Responders and non-responders to probiotic interventions

“…However, the presence of fecal galN-pyrazines in nonresponders, but not responders, allows the separation of the two groups by a fecal biomarker. 3 In terms of probiotics, if a Crohn disease patient has defective nucleotide-binding oligomerization domain (Nod)2 receptors, it is likely that they would not respond to lactobacilli probiotic treatment. 4 This should be investigated before a clinical study is performed to determine if any patients have Nod2 mutations and subject enrollment criteria modified appropriately.…”

In‐vivo‐Festphasen‐Mikroextraktion in der Metabolomik: Möglichkeiten zur direkten Erforschung biologischer Systeme

“…[45] Beispielsweise untersuchten Coen et al das Metabolom von verschiedenen Kompartimenten, um die toxische Reaktion von Ratten auf die Verabreichung von Galactosaminen aufzuklären. [46] Diese Studie lieferte nicht nur interessante Einblicke in den Mechanismus der Toxizität von Galactosaminen, sondern illustrierte auch das Potenzial von Metabolomikstudien für das Studium der Unterschiede in den individuellen Reaktionen, da 25 % der Ratten nicht reagierten, während 75 % der Ratten verschiedene Stufen von Hepatotoxizität aufwiesen. Wir glauben, dass In-vivo-SPME bei solchen Studien eine wichtige Rolle spielen kann, da es eine wiederholte Probennahme im selben Tier zu verschiedenen Zeitpunkten und an verschiedenen Punkten (z.…”