Top image

Contact us


For any enquiries related to the Pharmacology and Toxicology research area, please contact

Fiona Pereira
CSM Research Manager
csm@imperial.ac.uk

+44 (0)20 7594 3197

Exploring xenobiotic metabolism and action

Understanding both the beneficial and deleterious effects of environmental stressors of all kinds (therapeutics, pollutants, poisons, etc.) is a key focus of researchers in the Division of CSM. Drawing on the wealth of expertise and knowledge from across the Division and through close collaborations, CSM pioneered the use of metabolic phenotyping tools in understanding responses to chemical and other exposures, as well as characterising the metabolic fate of exogenous chemical compounds. 

The complementary, high-resolution analytical platforms of NMR spectroscopy and MS allow CSM to conduct high-throughput analysis of biological samples generated in toxicological and drug metabolism studies. These perform particularly well in the analysis of small molecule metabolites, and permit efficient characterisation of complex drug metabolism and endogenous responses using similar technological platforms. Small molecule studies are complemented with an extensive programme of molecular toxicology, integrating multiplexed cytokine assays, oligonucleotide analysis and next-generation sequencing.


Find out more about our key focus areas:

Accordion widget

Drug Metabolism

Imperial has a long history of making contributions to pharmaceutical development, including the discovery of penicillin at St Mary's Hospital Medical School in 1928. A major part of understanding the action of therapeutic agents and associated toxicity relies on the characterisation of their metabolic fate. Today, researchers in CSM engage in a range research activities with drug metabolism at the core. These include projects focused on evaluating emerging models for preclincal safety assessment, computational modeling for prediction of metabolism stability, and informatics approaches for mining publically available datasets. 

The performance of analytical assays for characterising drug metabolism has radically improved in recent years as a consequence of the step-change across the fields of liquid chromatography, mass spectrometry, and NMR spectroscopy, permitting the fate of compounds to be studied in fine details. Coupled with advances in molecular biology techniques, there are now new ways to probe drug metabolism, and understand more subtle relationships with observed toxicological responses.

The Division has been instrumental in the reformation of the Drug Metabolism Group, aimed at bringing together researchers from across academic, industry, third sector and government, to share knowledge and develop collaborative ideas in the fields of toxicology, pharmacology, and drug metabolism. For more information, contact the DMG Committee: admin@thedrugmetabolismgroup.com

Molecular Toxicology

Research activity in the area of molecular toxicology within CSM is led by Professor Nigel Gooderham. The group are exploring mechanisms of chemical toxicity, genetic toxicity and carcinogenesis and the role of non-coding RNA in toxicity.  The research is underpinned by mechanistic studies in a variety of in vitro models, using cell culture, molecular biology and biochemistry as well as high end spectroscopic analytical approaches.  The programme explores the toxicity and genotoxicity of both small molecular weight chemicals and oligonucleotides. Current projects include:

  • Chemical and miRNA mediated gene expression in cancer stem cells and gastric cancer
  • Understanding chemical-induced genotoxicity in 3D cell culture models
  • The role of inflammation and non-coding RNA in chemical-induced carcinogenesis
  • Genetic toxicology of low-dose chemical mixtures and therapeutic oligonucleotides

Environmental Toxicology and Exposome

The environment in which we live and work has a large impact on our health and influences our risk of disease. Exposure to chemicals, radiation, noise and other environmental factors are important to consider, and are now holistically combined into the concept of a human 'exposome', the environmental equivalent of the human genome. Establishing the linkage between exposures and disease outcomes forms an important part of epidemiological exposome research and informing science-based policy decisions. The establishment of omics technologies as tools for large-scale profiling of human biofluid samples has recently been achieved by researchers in CSM in collaboration with others at Imperial College and worldwide, and has opened up the possibilities for scientific discoveries and translation in several main areas:

  • Provide individual-level measurements to complement small-area and group measurements
  • Efficient discovery of biomarkers through metabolism-wide association studies
  • Mechanistic relevance to exposure and disease
  • Use of sentinel species for environmental monitoring
  • Potential for direct impact on environmental health policy

Earth

Key members within Pharmacology and Toxicology

Search or filter publications

Filter by type:

Filter by publication type

Filter by year:

to

Results

  • Showing results for:
  • Reset all filters

Search results

  • JOURNAL ARTICLE
    Akingbasote JA, Foster AJ, Jones HB, David R, Gooderham NJ, Wilson ID, Kenna JGet al., 2017,

    Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid

    , Toxicology Research, Vol: 6, Pages: 81-88, ISSN: 2045-452X

    © The Royal Society of Chemistry. Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit no functional expression of hepatic cytochrome P450 (P450) when compared to wild type (WT) mice, but have normal hepatic and extrahepatic expression of other biotransformation enzymes. We have assessed the utility of HRN™ mice for investigation of the role of metabolic bioactivation in liver toxicity caused by the nonsteroidal anti-inflammatory drug (NSAID) fenclozic acid. In vitro studies revealed significant NADPH-dependent (i.e. P450-mediated) covalent binding of [ 14 C]-fenclozic acid to liver microsomes from WT mice and HRN™ mice, whereas no in vitro covalent binding was observed in the presence of the UDP-glucuronyltransferase cofactor UDPGA. Oral fenclozic acid administration did not alter the liver histopathology or elevate the plasma liver enzyme activities of WT mice, or affect their hepatic miRNA contents. Livers from HRN™ mice exhibited abnormal liver histopathology (enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration, necrosis, inflammatory cell infiltration) and plasma clinical chemistry (elevated alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities). Modest apparent improvements in these abnormalities were observed when HRN™ mice were dosed orally with fenclozic acid for 7 days at 100 mg kg −1 day −1 . Previously we observed more marked effects on liver histopathology and integrity in HRN™ mice dosed orally with the NSAID diclofenac for 7 days at 30 mg kg −1 day −1 . We conclude that HRN™ mice are valuable for assessing P450-related hepatic drug biotransformation, but not for drug toxicity studies due to underlying liver dysfunction. Nonetheless, HRN™ mice may provide novel insights into the role of inflammation in liver injury, thereby aiding its treatment.

  • JOURNAL ARTICLE
    Cohen SM, Fukushima S, Gooderham NJ, Guengerich FP, Hecht SS, Rietjens IMCM, Smith RL, Bastaki M, Harman CL, McGowen MM, Valerio LG, Taylor SVet al., 2017,

    Safety evaluation of substituted thiophenes used as flavoring ingredients.

    , Food Chem Toxicol, Vol: 99, Pages: 40-59

    This publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS™ status. In the absence of these data, the compound was removed from the FEMA GRAS list.

  • JOURNAL ARTICLE
    Gray N, Zia R, King A, Patel VC, Wendon J, McPhail MJW, Coen M, Plumb RS, Wilson ID, Nicholson JKet al., 2017,

    High-Speed Quantitative UPLC-MS Analysis of Multiple Amines in Human Plasma and Serum via Precolumn Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate: Application to Acetaminophen-Induced Liver Failure

    , ANALYTICAL CHEMISTRY, Vol: 89, Pages: 2478-2487, ISSN: 0003-2700
  • JOURNAL ARTICLE
    Harling L, Lambert J, Ashrafian H, Darzi A, Gooderham NJ, Athanasiou Tet al., 2017,

    Elevated serum microRNA 483-5p levels may predict patients at risk of post-operative atrial fibrillation

    , EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, Vol: 51, Pages: 73-78, ISSN: 1010-7940
  • JOURNAL ARTICLE
    Inglese P, McKenzie JS, Mroz A, Kinross J, Veselkov K, Holmes E, Takats Z, Nicholson JK, Glen RCet al., 2017,

    Deep learning and 3D-DESI imaging reveal the hidden metabolic heterogeneity of cancer

    , CHEMICAL SCIENCE, Vol: 8, Pages: 3500-3511, ISSN: 2041-6520

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-t4-html.jsp Request URI: /respub/WEB-INF/jsp/search-t4-html.jsp Query String: id=921&limit=5&respub-action=search.html Current Millis: 1506288356713 Current Time: Sun Sep 24 22:25:56 BST 2017