Drug Metabolism & Toxicology
Metabonomics can report on biochemical changes at the cellular, tissue and system level and are ideally suited to studying small molecule perturbations caused by toxicity.
The same profiling tools are also ideally suited to characterising the metabolism of many xenobiotics which are small molecules, and can often reveal the chemical species responsible for observed pathologies.
Developing Expert Systems for Toxicity Prediction
The Section leads the COMET consortium, which has generated a large biological database and tissue samples spanning a range of organ- and mechanism-specific toxicities in the rat and mouse. See the COMET project page for more details.
Molecular Mechanisms of Carcinogenesis
Biomolecular Medicine has a strong background in using molecular toxicology, led primarily by Prof. Nigel Gooderham to investigate the mechanisms involved in chemical carcinogenesis, and in cancer progression processes. Additionally, research into the metabolism of chemical carcinogens and methods of monitoring exposure to such compounds feature as substantial parts of the Biomolecular Medicine research programme in molecular toxicology.
Investigating the Biochemical Mechanisms of Renal Disease in Man and Animals
Kidney disease is a common cause of disablement and death in the western world and may have a variety of complex aetiologies and sequelae. The most important single cause of end-stage renal failure (and consequent renal transplantation) is Polycystic Kidney Disease (affects 1 in 500 people). The mechanisms, aetiology and pathogenesis of PKD are poorly understood and there is no effective treatment other than transplantation. Therefore, we are investigating the biochemical composition of cystic fluids by NMR and studying the molecular interactions of the components in the intact fluid in order to understand better the dynamic chemical processes involved in cyst growth. Important medical problems may arise following renal transplantation (the most effective treatment for end-stage renal damage) in particular the ability of the clinician to distinguish kidney rejection from immunosuppressant drug toxicity. We are currently using NMR to investigate renal biochemical perturbations in human subjects who have poor graft function with a view to improving the sensitivity of current diagnostic techniques and so improve the patients' prognosis. We are also using pattern recognition methods to integrate and analyse NMR generated and conventional clinical chemical data sets in order to improve currently used diagnostic criteria for renal functional assessment.
In parallel experimental studies we are attempting to model certain kidney diseases in laboratory animals with particular emphasis on a mechanistic study of the biochemical sequelae of experimentally-induced renal medullary damage and the relationship between papillary necrosis and urinary composition. Renal papillary damage is a common long term side effect of widely used non steroidal anti-inflammatory agents such as ibuprofen, aspirin and naproxen. The overall aim of this work is to elucidate the relationships between damage to cells in specific regions of the nephron and changes in low molecular weight urinary components, particularly those acting as novel markers of toxicity, and to generate new biochemical information which will be relevant to clinical situations in which renal function is perturbed.
Key Project
Key Recent Publications
Coen M, Want EJ, Clayton TA, Rhode CM, Hong YS, Keun HC, Cantor GH, Metz AL, Robertson DG, Reily MD and others. 2009. Mechanistic aspects and novel biomarkers of responder and non-responder phenotypes in galactosamine-induced hepatitis. J Proteome Res 8(11):5175-87.
Guo Q, Sidhu JK, Ebbels TMD, Rana F, Spurgeon DJ, Svendsen C, Sturzenbaum SR, Kille P, Morgan AJ, Bundy JG. 2009. Validation of metabolomics for toxic mechanism of action screening with the earthworm Lumbricus rubellus. Metabolomics 5(1):72-83.
Bollard ME, Contel NR, Ebbels TM, Smith L, Beckonert O, Cantor GH, Lehman-McKeeman L, Holmes EC, Lindon JC, Nicholson JK and others. 2009. NMR-Based Metabolic Profiling Identifies Biomarkers of Liver Regeneration Following Partial Hepatectomy in the Rat. J Proteome Res. 9(1):59-69.
Hughes SL, Bundy JG, Want EJ, Kille P, Sturzenbaum SR. 2009. The metabolomic responses of Caenorhabditis elegans to cadmium are largely independent of metallothionein status, but dominated by changes in cystathionine and phytochelatins. J Proteome Res 8(7):3512-9.
Charalambous MP, Lightfoot T, Speirs V, Horgan K, Gooderham NJ. 2009. Expression of COX-2, NF-kappaB-p65, NF-kappaB-p50 and IKKalpha in malignant and adjacent normal human colorectal tissue. Br J Cancer 101(1):106-15.
Fede JM, Thakur AP, Gooderham NJ, Turesky RJ. 2009. Biomonitoring of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and its carcinogenic metabolites in urine. Chem Res Toxicol 22(6):1096-105.
Nicholson J, Keun H, Ebbels T. 2007. COMET and the challenge of drug safety screening. Journal of Proteome Research 6(11):4098-9.
Ebbels TMD, Keun HC, Beckonert OP, Bollard ME, Lindon JC, Holmes E, Nicholson JK. 2007. Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: The Consortium on Metabonomic Toxicology screening approach. Journal of Proteome Research 6(11):4407-22.
Ebbels TMD, Keun HC, Beckonert OP, Bollard ME, Lindon JC, Holmes E, Nicholson JK. 2007. Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: The Consortium on Metabonomic Toxicology screening approach. Journal of Proteome Research 6(11):4407-22.
