Project description:Using a Cebus capucinus model and after chronic copper oral administration, we assessed a global transcriptional liver adaptations induced by acutely challenging the animals with a unique high dose of oral acetaminophen (APAP).
Project description:Reddyhoff2015 - Acetaminophen metabolism and toxicity
This model examines acetaminophen metabolism and related hepatotoxicity. Multiple pathways associated with APAP metabolism has been included in the model. Using numerical, sensitivity and timescale analysis, key parameters involved in the toxicity has been identified. The model analysis highlights a critical acetaminophen dose in terms of the model parameters.
This model is described in the article:
Timescale analysis of a mathematical model of acetaminophen metabolism and toxicity.
Reddyhoff D, Ward J, Williams D, Regan S, Webb S
J Theor Biol. 2015 Dec 7;386:132-46.
Abstract:
Acetaminophen is a widespread and commonly used painkiller all over the world. However, it can cause liver damage when taken in large doses or at repeated chronic doses. Current models of acetaminophen metabolism are complex, and limited to numerical investigation though provide results that represent clinical investigation well. We derive a mathematical model based on mass action laws aimed at capturing the main dynamics of acetaminophen metabolism, in particular the contrast between normal and overdose cases, whilst remaining simple enough for detailed mathematical analysis that can identify key parameters and quantify their role in liver toxicity. We use singular perturbation analysis to separate the different timescales describing the sequence of events in acetaminophen metabolism, systematically identifying which parameters dominate during each of the successive stages. Using this approach we determined, in terms of the model parameters, the critical dose between safe and overdose cases, timescales for exhaustion and regeneration of important cofactors for acetaminophen metabolism and total toxin accumulation as a fraction of initial dose.
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Project description:Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage defects displaying identical phenotypic alterations and carrying mutations in genes known to be involved in copper transport. Besides disease initiation and progression of copper accumulation, the molecular mechanisms and pathways involved in copper accumulation and eventually progression towards copper associated chronic hepatitis still remains unclear. Using liver tissue of Labrador retrievers in different stages of copper-associated hepatitis, expression levels targeted at candidate genes as well as transcriptome microarrays, have shed light on involved molecular pathways. At the initial phase, viz. increased hepatic copper levels, transcriptomic alterations in livers revealed enrichment for cell adhesion, developmental, inflammatory, and cytoskeleton pathways. Upregulation of targeted MT1A and COMMD1 mRNA shows the livers first response to rising intrahepatic copper concentrations. In livers with copper-associated hepatitis mainly an activation of inflammatory pathways is detected. Once the hepatitis is in the chronic stage, transcriptional differences are found in cell adhesion adaptations and cytoskeleton remodelling. In view of the high similarities in hepatopathies between men and dog extrapolation of these dog data into human biomedicine seems feasible.
Project description:Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant-free survival of APAP-induced acute liver failure (ALF) patients. We used affy microarrays to explore the mechanisms of transcriptional expression in YAP-KO mice after 300mg/kg APAP overdose.
Project description:The gene expression profiles were analyzed of HuH-7 cells treated with cytotoxic agents, such as acetaminophen, arsenic or copper, along with cells that were treated for potential benefits with either caffeine or exosomes isolated from pooled human sera