Gut Microbial Metabolites and Hepatic Xenobiotic Metabolism: A High Throughput Screening Approach
Poster Sep 19, 2014
Glynn Martin, James Sidaway, Jonathan Swann
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.
A New Method for Analyzing MSe/All Ions Fragmentation in Xenobiotic Metabolism StudiesPoster
During early drug discovery, the study of metabolism plays an essential role in determining which drug candidates move forward into development and later stages. As an alternative to traditional Data Dependent Acquisition (DDA), the use of MSE/All Ions Fragmentation (AIF) has become common in metabolite identification workflows for the analysis of metabolic hot spots. Here we present a solution for analysis of MSE/AlF in metID studies.READ MORE
Extracorporeal shockwave therapy accelerates motor axon regeneration despite a phenotypically mismatched environmentPoster
A femoral nerve defect model was adapted for the evaluation of proregenerative effects of extracorporeal shockwave therapy (ESWT). Functional evaluation, histology and qRT-PCR data show differences between sensory and motor-derived nerve transplants and a pro-regenerative effect of ESWT. These data provide evidence for the clinical application of ESWT after autologous nerve transplantation as a novel non-invasive method.READ MORE