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Gut Microbial Metabolites and Hepatic Xenobiotic Metabolism: A High Throughput Screening Approach
EP22257
Poster Title: Gut Microbial Metabolites and Hepatic Xenobiotic Metabolism: A High Throughput Screening Approach
Submitted on 19 Sep 2014
Author(s): Glynn Martin, James Sidaway, Jonathan Swann
Affiliations: University of Reading, AstraZeneca
This poster was presented at Metabomeeting 2014
Poster Views: 1,768
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Poster Information
Abstract: Idiosyncratic drug responses leading to drug induced liver injury (DILI) occur in 15% of patients receiving drug treatments. These idiosyncratic drug reactions cannot be explained or predicted. The gut microbiome is highly host specific and is known to influence the host metabolic system including xenobiotic metabolism. Here, the potential for gut microbial-associated metabolites to impact on host drug metabolism and toxicity was explored using a novel exploratory pipeline. Candidate microbial metabolites were identified using two antibiotic-treated rodent models and a 1H NMR spectroscopy-based metabonomic approach. The modulatory potential of each metabolite was then evaluated using a high throughput in vitro screening approach following co-administration with paracetamol. Hepatic SV40 large T-antigen immortalized human liver epithelial (THLE) cell lines were used including a subline transfected with CYP2E1, a major drug metabolising enzyme. Twelve microbial metabolites were screened and one microbial metabolite, 4-cresyl, was found to increase toxicity when dosed to THLE-CYP2E1 cells. Co-administration of paracetamol with 4-cresyl resulted in a greater toxic effect compared to an equivalent dose of paracetamol or 4-cresyl alone. Through this novel screening approach microbial-associated metabolites have been identified and their potential to modulate host xenobiotic metabolism, and therefore contribute to idiosyncratic drug responses, has been evaluated.Summary: This poster highlights the combination of metabonomics and high throughput screening by the identification of gut microbial metabolites and a screening assay designed to determine their cytotoxicity to liver-like cell cultures.References: Report abuse »
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