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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:

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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

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Key members within Pharmacology and Toxicology

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  • JOURNAL ARTICLE
    Pickup K, Martin S, Partridge EA, Jones HB, Wills J, Schulz-Utermoehl T, McCarthy A, Rodrigues A, Page C, Ratcliffe K, Sarda S, Wilson IDet al., 2017,

    Acute liver effects, disposition and metabolic fate of [14C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice.

    , Arch Toxicol, Vol: 91, Pages: 2643-2653

    The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).

  • JOURNAL ARTICLE
    P Dickie A, Wilson CE, Schreiter K, Wehr R, D Wilson I, Riley Ret al., 2017,

    Lumiracoxib metabolism in male C57bl/6J mice: characterisation of novel in vivo metabolites.

    , Xenobiotica, Vol: 47, Pages: 538-546

    1. The pharmacokinetics and metabolism of lumiracoxib in male C57bl/6J mice were investigated following a single oral dose of 10 mg/kg. 2. Lumiracoxib achieved peak observed concentrations in the blood of 1.26 + 0.51 μg/mL 0.5 h (0.5-1.0) post-dose with an AUCinf of 3.48 + 1.09 μg h/mL. Concentrations of lumiracoxib then declined with a terminal half-life of 1.54 + 0.31 h. 3. Metabolic profiling showed only the presence of unchanged lumiracoxib in blood by 24 h, while urine, bile and faecal extracts contained, in addition to the unchanged parent drug, large amounts of hydroxylated and conjugated metabolites. 4. No evidence was obtained in the mouse for the production of the downstream products of glutathione conjugation such as mercapturates, suggesting that the metabolism of the drug via quinone-imine generating pathways is not a major route of biotransformation in this species. Acyl glucuronidation appeared absent or a very minor route. 5. While there was significant overlap with reported human metabolites, a number of unique mouse metabolites were detected, particularly taurine conjugates of lumiracoxib and its oxidative metabolites.

  • 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
  • JOURNAL ARTICLE
    Maitre L, Lau C-HE, Vizcaino E, Robinson O, Casas M, Siskos AP, Want EJ, Athersuch T, Slama R, Vrijheid M, Keun HC, Coen Met al., 2017,

    Assessment of metabolic phenotypic variability in children's urine using H-1 NMR spectroscopy

    , SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
  • JOURNAL ARTICLE
    Nijhuis A, Thompson H, Adam J, Parker A, Gammon L, Lewis A, Bundy JG, Soga T, Jalaly A, Propper D, Jeffery R, Suraweera N, McDonald S, Thaha MA, Feakins R, Lowe R, Bishop CL, Silver Aet al., 2017,

    Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance

    , HUMAN MOLECULAR GENETICS, Vol: 26, Pages: 1552-1564, ISSN: 0964-6906

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.

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