Using humanised transgenic models to study anti-cancer drug metabolism and disposition
Division of Cancer Research
Jacqui Wood Cancer Centre
University of Dundee
James Arrott Drive
Ninewells Hospital And Medical School
+(44) 01382 383130
Colin Henderson received his BSc (Hons) (1981) in Biochemistry and PhD (1985) from the Medical Faculty, both University of Edinburgh. First postdoctoral position with the MRC Reproductive Biology Unit in Edinburgh (1984-1987); joined group of Roland Wolf (1987) at Imperial Cancer Research Fund (later Cancer Research UK) at the University of Edinburgh. Relocated as Chief Scientific Officer with Cancer Research UK group to Biomedical Research Centre, University of Dundee in 1993; became Staff Scientist with Cancer Research UK group (1999). Honorary Senior Lecturer in the Biomedical Research Centre (2000); appointed as Senior Lecturer at the University of Dundee in Division of Cancer Research, Medical Research Institute in April 2011.
Transgenic technology has the potential to revolutionise the fields of toxicology and drug metabolism; the ability to manipulate genetically the expression of individual drug metabolising enzymes in order to better understand their function(s) could lead to the development of new drugs for the treatment of diseases such as cancer, as well as the optimisation of treatment regimes with existing drugs. I have worked in this area for nearly 20 years, developing a number of transgenic mouse models to facilitate the study of how drug metabolising enzymes protect us from the chemically challenging environment in which we live, and how the expression of these enzymes is related to the aetiology of cancer.
My current research interests centre around the post-translational modification of proteins on cysteine residues by addition of the abundant cellular thiol glutathione, and the involvement of glutathione transferase P (GSTP) in this process. GSTP is expressed at elevated levels in a number of animal and human tumours, and in cell lines made resistant to a variety of drugs. Little, however, is known about the endogenous role(s) of this enzyme. We were the first to describe deletion of GSTP in mice, which are apparently phenotypically normal, although they display an increased resistance to acetaminophen involving a mechanism(s) which have not yet been fully elucidated, but which may involve GSTP acting as an inhibitor of Jun kinase, thus effecting cellular signalling cascades and the regulation of stress response genes. GSTP null mice also have significantly higher levels of tumour formation in the skin or lungs, when challenged chemically, or in the colon in a genetic model (APCMin). Gene expression profiling suggests a role for GSTP in regulating innate immunity and inflammatory processes, which is the subject of ongoing investigation.
More than 100 proteins have been shown to be glutathionylated, including several involved in energy metabolism and the cytoskeleton. However, the extent to which proteins are glutathionylated/deglutathionylated, under what circumstances and the physiological significance, remains to be determined. My research will use a variety of in vitro and in vivo approaches, including cell lines and transgenic mice, to investigate and characterise the ‘glutathiome’ and the cellular consequences arising from these protein modifications.
I am also involved in an EU-funded Innovative Medicines Initiative (MARCAR - Markers of Carcinogenesis) in which transgenic reporter mouse lines are used to investigate the relationship between oxidative stress and non-genotoxic carcinogenesis, with a view to identifying early biomarkers. This is a collaboration between academic centres and pharmaceutical partners across Europe.
I am a co-grant holder (with Professor Roland Wolf) in an ERC Advanced Investigator award (REDOX) looking at the role of oxidative stress in disease aetiology and development of new methods of detecting oxidative stress, including non-invasive in vivo systems.
“Activation status of the Pregnane X Receptor (PXR) influences Vemurafenib availability in humanized mouse models” MacLeod, A.K., McLaughlin, L.A., Henderson, C.J. & Wolf, C.R.Cancer Res. (2015) (In Press)
“Altered protein S-glutathionylation identifies a potential mechanism of resistance to acetaminophen-induced hepatotoxicity" McGarry D.J., Chakravarty, P., Wolf C.R. & Henderson C.J. J. Pharmacol. Ther. (2015) In Press oi:10.1124/jpet.115.227389
“Defining human pathways of drug metabolism in vivo through the development of a multiple humanized mouse model” Scheer, N., Kapelyukh, Y, Rode, A., Oswald, S., Busch, D., Mclaughlin, L.A., Lin, D., Henderson, C.J., & Wolf C.R. Drug Metabolism Disp. (2015) In Press
“The Role of Protein-protein and Protein-membrane Interactions in P450 Function” Henderson, C.J., McLaughlin, L.A., Wolf, C.R. et al., (2015) Symposium Report, Drug Metab. Disp. In Press
“Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action’ Kostov, R.V., Knatko, E.V., McLaughlin, L.A., Henderson, C.J., Suqing Zheng, S., Huang, J.T., Tadashi Honda, T. & Dinkova-Kostova, A. Biochem. Biophys. Res. Comm. (2015) In Press
‘Proteome-wide identification and quantification of S-glutathionylation targets in mouse liver’ McGarry D.J., Chen, W., Chakravarty, P., Lamont, D.J., Wolf C.R. & Henderson, C.J. Biochem. J. (2015) 469, 25-32
‘Evidence that the capacity of non-genotoxic carcinogens to induce oxidative stress is subject to marked variability’ Henderson, C.J., Cameron A.R., Chatham L., Stanley L.A., Wolf C.R. Toxicol. Sci. (2015) 145, 138-48
‘Cytochrome b5 is a major determinant of human cytochrome P450 CYP2D6 & CYP3A4 activity in vivo’ Henderson C.J., McLaughlin, L.A. & Wolf C.R. Mol. Pharmacol. (2015) 87, 733-9
‘The Hepatic Reductase Null (HRN™) and Reductase Conditional Null (RCN) mouse models as suitable tools to study metabolism, toxicity and carcinogenicity of environmental pollutants’ Arlt, V.M., Henderson, C.J., Wolf, C.R., Stiborova, M. & Phillips, D.H. Toxicol. Res. (2015) 4, 548-562
‘Glutathione transferases P1/P2 regulate the timing of signalling pathway activations and cell cycle progression during mouse liver regeneration’ Corlu A., Pajaud J., Ribault C., Ben Mosbah I., Rauch C., Henderson, C.J., Bellaud P., Aninat C., Loyer P., Morel F., Cell Death & Disease (2015) 6, e1598; doi:10.1038/cddis.2014.562
‘An Enhanced in vivo SILAC model for Quantification of Drug Metabolism Enzymes’ MacLeod, A.K., Fallon, P., Sharp, S., Henderson, C.J., Wolf, C.R. & Huang, J.T. Mol. Cell. Proteomics (2015) 14, 750-60
"Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability’ Henderson C.J., McLaughlin, L.A., McLaren, A.W. & Wolf C.R. Biochem. J. (2015) 65, 479-88
‘HDAC inhibitors increase NRF2-signalling in tumour cells and blunt the efficacy of co-administered cytotoxic agents’ McMahon, M.J.M., Campbell, K., MacLeod, A.K., McLaughlin, L.A., Henderson C.J. & Wolf C.R. PLoS One 2014;9(11):e114055.
‘Cytochrome b5 and epoxide hydrolase contribute to benzo[a]pyrene-DNA adduct formation catalyzed by cytochrome P450 1A1 under low NADPH:P450 oxidoreductase conditions’ Stiborova, M., Moserova, M., Cerna, V., Indra, R., Dracinsky, M., Sulc, M., Henderson, C. J., Wolf, C. R., Schmeiser, H. H., Phillips, D. H., Frei, E. & Arlt, V. M. Toxicology (2014) 318, 1-12
‘Deletion of 30 murine Cytochrome P450 genes results in viable mice with compromised drug metabolism’ Scheer, N., McLaughlin, L. A., Rode, A., Macleod, A. K., Henderson, C. J. & Wolf, C. R. Drug Metab. Dispos. (2014) 42, 1022-1030
‘A targeted in vivo SILAC approach for quantification of drug metabolism enzymes: regulation by the constitutive androstane receptor’ MacLeod, A. K., Zang, T., Riches, Z., Henderson, C. J., Wolf, C. R. & Huang, J. T. J. Proteome Res. (2014) 13, 866-874
‘Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane X receptors’ Luisier, R., Lempiainen, H., Scherbichler, N., Braeuning, A., Geissler, M., Dubost, V., Muller, A., Scheer, N., Chibout, S. D., Hara, H., Picard, F., Theil, D., Couttet, P., Vitobello, A., Grenet, O., Grasl-Kraupp, B., Ellinger-Ziegelbauer, H., Thomson, J. P., Meehan, R. R., Elcombe, C. R., Henderson, C. J., Wolf, C. R., Schwarz, M., Moulin, P., Terranova, R. & Moggs, J. G. Toxicol. Sci (2014) 139, 501-511
‘In Vivo Regulation of Human Glutathione Transferase GSTP by Chemopreventive Agents’ Henderson, C. J., McLaren, A. W. & Wolf, C. R. Cancer Res. (2014) 4378-4387
‘Phenobarbital-Mediated Tumor Promotion in Transgenic Mice with Humanized CAR and PXR’ Braeuning, A., Gavrilov, A., Brown, S., Wolf, C. R., Henderson, C. J. & Schwarz, M. Toxicol. Sci. (2014) 140, 259-70
‘A Role for Cytochrome b5 in the in vivo Disposition of Anti-cancer and Cytochrome P450 Probe Drugs in Mice’ Henderson, C.J., MacLaughlin, L.A., Finn, R.D., Ronseuax, S., Kapelyukh, Y. & Wolf, C.R. Drug Metab. Dispos. (2014) 42, 70-77
‘Pyrethroid activity-based probes for profiling cytochrome P450 activities associated with insecticide interactions’ Ismail, H. M., O'Neill, P. M., Hong, D. W., Finn, R. D., Henderson, C. J., Wright, A. T., Cravatt, B. F., Hemingway, J. & Paine, M. J. Proc Natl Acad Sci U S A. (2013) 110, 19766-19771
‘NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology’ Riddick D.S., Ding X., Wolf C.R., Porter T.D., Pandey A.V., Zhang Q.Y., Gu J., Finn R.D., Ronseaux S., McLaughlin L.A., Henderson C.J., Zou L., Flück C.E. Drug Metab. Dispos. (2013) 41, 12-23
‘Evidence that cytochrome b5 and cytochrome b5 reductase can act as sole electron donors to the hepatic cytochrome P450 system’ Henderson, C.J., McLaughlin, L.A., & Wolf, C.R. Mol. Pharmacol. (2013) 83, 1209-17
‘The Involvement of Mitochondrial Amidoxime Reducing Components 1 and 2 and Mitochondrial Cytochrome b5 in N-Reductive Metabolism in Human Cells’ Plitzko B., Ott G., Reichmann D., Henderson C.J., Wolf C.R., Mendel R., Bittner F., Clement B., Havemeyer A. J. Biol. Chem. (2013) 288, 20228-20237
Undergraduate students: I have delivered lectures and practical classes to science and medical students, mainly in the area of toxicology, drug metabolism and transgenic models. I currently participate in MRes Cancer, Level 4 Cancer Biology and SSC components for Medicine and Pharmacology.
Postgraduate students: I have been involved in the supervision of a number of graduate students; I am currently second supervisor to one graduate student.
PhD & MSc Examinations: I have been Convenor or Internal Examiner for MSc and PhD theses in the Medical School, and External Examiner at a number of UK academic institutions.
Neil Shearing ‘The importance of transcription factor binding sites and methylation status in regulating differential GSTP1 expression in drug resistant and drug sensitive human breast carcinoma cell lines’ (2000)
Claire Scott ‘Investigating the induction of hepatic P450s in the Hepatic Reductase Null Mouse’ (2006)
Emily Fraser ‘Investigating the role of CAR and PXR in the regulation of cytochrome P450s and other drug metabolizing enzymes by anti-cancer drugs using novel humanised mouse models’ (2013)
David McGarry ‘Non-catalytic mechanisms involved in Glutathione S-transferase Pi mediated cytoprotection’ (2013)
Cheryl Wood 'Mouse Hepatitis virus: prevalence and infectivity' (2013)
‘Prediction of cancer development: translation of molecular events to the clinic’
- British Toxicology Society Annual Congress, Manchester, April 2016
- British Toxicology Society and British Pharmacological Society joint meeting, Edinburgh, October 2015
‘Transgenic reporter mouse lines to investigate the relationship between oxidative stress and non-genotoxic carcinogenesis’
- European Environmental Mutagen Society (EEMS) 2015, Prague, August 2015
‘The role of Cytochrome b5 in drug metabolism and disposition’
- 19th International Conference on Cytochrome P450, Tokyo, Japan, June 2015
‘Humanised transgenic mouse models in drug metabolism and disposition’
- 13th European ISSX meeting, Glasgow, June 2015
- Chair, session ‘Humanised animals in Drug Development’
‘Transgenic mouse models to define the in vivo role of Cytochrome b5 in drug metabolism and disposition’
- 20th International Symposium on Microsomes & Drug Oxidations, Stuttgart, Germany, May 2014.
‘Humanised models of drug metabolism’
- to the meeting of the Scottish RDG, Edinburgh, March 2012
‘Application of Transgenic Models in Metabolism and Toxicology’
- to the Third Annual Lhasa symposium – New horizons in toxicity prediction - Cambridge, September 2012