Dr Nick Plant
Reader in Molecular Toxicology
Email: n.plant@surrey.ac.uk
Phone: Work: 01483 68 6412
Room no: 12 AY 04
Office hours
I'm in my office most days but due to frequent meeting commitments it's difficult to specify exact times. If my door is open you are more than welcome to drop in. Alternatively, you can email me to set up a meeting
Further information
Biography
STOP PRESS:
March 2013: Read my latest publication on Polymer Drug Delivery here. The attachment of drugs (chemical or biological in nature) to nanoparticles and polymers is an area of intense study at present. Through such conjugation it is possible to improve the action of drugs through a number of mechanisms; enhanced stability, targeted distribution, and multi-functionalisation to produce combination treatments. In this paper, we use a site-specific conjugation method (Sortase A) to attach a DNA binding protein to a self-assembling peptide hydrogel. Importantly, we demonstrate that DNA binding activity is maintained following conjugation, an important first stage in the production of bioactive polymer therapeutics
November 2012: Read my latest publication on the seizure control potential of a range of medium chain fatty acids here. The medium chain triglyceride (MCT) ketogenic diet is used extensively for treating refractory childhood epilepsy, however it's mechanism of action is unclear. In this paper, we compare the potency of an established epilepsy treatment, Valproate (VPA), with a range of MCT diet-associated fatty acids (and related branched compounds), using in vitro seizure and in vivo epilepsy models. Our data therefore implicates medium chain fatty acids in the mechanism of the MCT ketogenic diet, and highlights a related new family of compounds that are more potent than VPA in seizure control with a reduced potential for side effects. As such, these compounds represent potential novel targets for the development of new seizure control therapies.
Guildford BrightClub: Bright Club is the thinking person's variety night, blending comedy, music, art, new writing, science, performance, and anything else that can happen on a stage.For an alternative, slightly irreverent and sometimes rude, take on science, visit our YouTube site.
PERSONAL PROFILE:
I have 15 year’s experience researching the coordination of cellular responses to xenobiotic challenge. My research has focussed on members of the super-family of nuclear receptors, which act as ligand-activated transcription factors, sensing their cellular surroundings and coordinating network responses to any disruption of homeostasis. In particular, I have championed the understanding of nuclear receptor interactions, including the pregnane-X receptor (PXR; the main nuclear receptor responsible for cellular response to xenobiotic challenge), the glucocorticoid receptor (GR), vitamin D receptor (VDR), peroxisome proliferator activated receptors (PPARα/β/γ) and Aryl hydrocarbon receptor (AhR).
I teach aspects of drug metabolism and toxicology to many different student groups, from undergraduate biochemists to continuing professional development courses. In addition to teaching the basic theory, I hope to pass on my enthusiasm and enjoyment of these subjects. Learning about how drugs are designed, and how we can ensure that they are safe when given to patients, is a subject that should teach everyone how far we have come in understanding and treating diseases in the last few years, but also how far we still have to go...
EDUCATION AND QUALIFICATIONS:
BSc (Hons) Biochemistry and Genetics University of Nottingham
PhD in Toxicology (BBSRC Case with ICI) University of Nottingham
Research Interests
My research interests focus on understanding how the body responds to chemical challenge. We are constantly exposed to thousands of chemicals, either deliberately (e.g. medicines) or accidentally (e.g. environmental contaminants), and these can have beneficial or adverse effects on the body. Through the use of state-of-the-art molecular and modelling techniques I aim to understand how the body responds to these chemicals, and how this can impact on endogenous processes. By understanding these complex networks of response we will hopefully be able to better predict individual response to chemical exposures, potentially leading to the safer, more effective use of therapeutic medicines.
My work can be split into three basic areas; understanding the role of nuclear receptors in coordinating body response to chemical challenge, using systems modelling to understand how these response networks actually work, and examining the impact of specific chemical classes (e.g. mood stabilisers). Please read below for a brief introduction to each area...
Nuclear Receptors
The nuclear receptors form a sub-family of the ligand-activated transcription factors, with 48 members being present in humans. Organism-wide tissue profiling has suggested that they play important roles in a number of biological functions, including development, steroidogenesis, energy homeostasis and lipid/drug metabolism. Nuclear receptors generally possess large ligand binding domains and show promiscuity in their activation profile, allowing them respond to a wide range of chemical stimuli, eliciting the most effective cellular response to fluxome alterations
Nuclear receptor research within the Centre for Toxicology at Surrey has two main aims. First, we are examining both the transcriptional regulation of nuclear receptors and their target genes. Second, in depth analysis of receptor functioning is underway to understand how they elicit their effects.
Systems Modelling
The human body is an amazingly complex system, able to respond to multiple different stimuli. In order to produce the most efficient response to any stimuli multiple biological systems may be activated, and it is the co-ordinated action of all of these systems that produces the ultimate response. To understand biological systems, and be able to predict their response it is thus necessary to model these entire systems.
At Surrey, we are taking two approaches to understanding these complex interaction networks. First, the use of –omic level analysis allows the characterisation of biological responses to chemical insult, including the identification of novel effects. Second, in silico modelling is used to recreate these biological networks, allowing a better understanding of how these networks function.
Mood Stabilising Drugs
Lithium chloride (LiCl) and the anticonvulsant valproate (VPA) are frontline treatments for the manic phase of bipolar disorder (BD), acting as mood stabilizers. In addition to this established therapeutic area, increasing support is being given towards the use of LiCl and VPA as general neuroprotective agents, with potential treatments including disorders such as Alzheimer’s or Parkinsonism although the molecular rationale behind this has yet to be elucidated. Both LiCl and sodium valproate have relatively small therapeutic indices and require high dosing levels to achieve efficacy. It is thus clear that in order to optimize the use of these agents and/or develop novel therapeutics it is necessary to fully understand their molecular actions.
Within the Centre for Toxicology at Surrey we are using molecular technologies to identify the molecular mechanisms of action of these two mood stabilising drugs, examining both their hepatic effects and neural effects.
Publications
Highlights
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(2012) 'Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner'. Elsevier Toxicology and Applied Pharmacology, 263 (1), pp. 7-13.Full text is available at: http://epubs.surrey.ac.uk/713799/
Abstract
The polychlorinated biphenyl group of possess high environmental persistence, leading to bioaccumulation and a number of adverse effects in mammals. Whilst coplanar PCBs elicit their toxic effects through agonism of the aryl hydrocarbon receptor; however, non-coplanar PCBs are not ligands for AhR, but may be ligands for members of the nuclear receptor family of proteins. To better understand the biological actions of non-coplanar PCBs, we have undertaken a systematic analysis of their ability to activate PXR and CAR-mediated effects Cells were exposed to a range of non-coplanar PCBs (99, 138, 153, 180 and 194), or the coplanar PCB77: Direct activation of PXR and CAR was measured using a mammalian receptor activation assay in human liver cells, with rifampicin and CITCO used as positive controls ligands for PXR and CAR, respectively; activation of target gene expression was examined using reporter gene plasmids for CYP3A4 and MDR1 transfected into liver, intestine and lung cell lines. Several of the non-coplanar PCBs directly activated PXR and CAR, whilst the coplanar PCB77 did not. Non-coplanar PCBs were also able to activate PXR/CAR target gene expression in a substitution- and tissue-specific manner. Non-coplanar PCBs act as direct activators for the nuclear receptors PXR and CAR, and are able to elicit transcriptional activation of target genes in a substitution- and tissue-dependent manner. Chronic activation of PXR/CAR is linked to adverse effects and must be included in any risk assessment of PCBs.
- . (2012) 'Seizure control by ketogenic diet-associated medium chain fatty acids'. Neuropharmacology,
- .
(2011) 'Conserved valproic-acid-induced lipid droplet formation in Dictyostelium and human hepatocytes identifies structurally active compounds'. The Company of Biologists Disease Models & Mechanisms, 5, pp. 231-240.doi: 10.1242/dmm.008391Full text is available at: http://epubs.surrey.ac.uk/239122/
Abstract
Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug valproic acid (VPA). In this study, we have developed a simple model system (Dictyostelium discoideum) to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24-hour period, giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minutes of VPA treatment. Using (3)H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in human hepatocytes (Huh7 cells) labelled with [(3)H]arachidonic acid. In addition, pharmacological inhibition of beta-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium could provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds that show liver toxicology.
- .
(2011) 'The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.'. Xenobiotica, England: 41 (7), pp. 519-529.Full text is available at: http://epubs.surrey.ac.uk/7258/
Abstract
The therapeutic class of HMG-CoA reductase inhibitors, the statins are central agents in the treatment of hypercholesterolaemia and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Although statin therapy is generally considered safe, a number of known adverse effects do occur, most commonly treatment-associated muscular pain. In vitro evidence also supports the potential for drug-drug interactions involving this class of agents, and to examine this a ligand-binding assay was used to determine the ability of six clinically used statins for their ability to directly activate the nuclear receptors pregnane X-receptor (PXR), farnesoid X-receptor (FXR) and constitutive androstane receptor (CAR), demonstrating a relative activation of PXR>FXR>CAR. Using reporter gene constructs, we demonstrated that this order of activation is mirrored at the transcriptional activation level, with PXR-mediated gene activation being pre-eminent. Finally, we described a novel regulatory loop, whereby activation of FXR by statins increases PXR reporter gene expression, potentially enhancing PXR-mediated responses. Delineating the molecular interactions of statins with nuclear receptors is an important step in understanding the full biological consequences of statin exposure. This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.
- .
(2010) 'Design principles of nuclear receptor signaling: how complex networking improves signal transduction'. NATURE PUBLISHING GROUP Molecular Systems Biology, 6 Article number 446 doi: 10.1038/msb.2010.102Full text is available at: http://epubs.surrey.ac.uk/2865/
Abstract
The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands. Molecular Systems Biology 6: 446; published online 21 December 2010; doi:10.1038/msb.2010.102
Journal articles
- . (2012) 'The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor'. Archives of Toxicology, 86 (10), pp. 1505-1514.
- .
(2012) 'Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner'. Elsevier Toxicology and Applied Pharmacology, 263 (1), pp. 7-13.Full text is available at: http://epubs.surrey.ac.uk/713799/
Abstract
The polychlorinated biphenyl group of possess high environmental persistence, leading to bioaccumulation and a number of adverse effects in mammals. Whilst coplanar PCBs elicit their toxic effects through agonism of the aryl hydrocarbon receptor; however, non-coplanar PCBs are not ligands for AhR, but may be ligands for members of the nuclear receptor family of proteins. To better understand the biological actions of non-coplanar PCBs, we have undertaken a systematic analysis of their ability to activate PXR and CAR-mediated effects Cells were exposed to a range of non-coplanar PCBs (99, 138, 153, 180 and 194), or the coplanar PCB77: Direct activation of PXR and CAR was measured using a mammalian receptor activation assay in human liver cells, with rifampicin and CITCO used as positive controls ligands for PXR and CAR, respectively; activation of target gene expression was examined using reporter gene plasmids for CYP3A4 and MDR1 transfected into liver, intestine and lung cell lines. Several of the non-coplanar PCBs directly activated PXR and CAR, whilst the coplanar PCB77 did not. Non-coplanar PCBs were also able to activate PXR/CAR target gene expression in a substitution- and tissue-specific manner. Non-coplanar PCBs act as direct activators for the nuclear receptors PXR and CAR, and are able to elicit transcriptional activation of target genes in a substitution- and tissue-dependent manner. Chronic activation of PXR/CAR is linked to adverse effects and must be included in any risk assessment of PCBs.
- .
(2012) 'Characterization of the temporal induction of hepatic xenobiotic-metabolizing enzymes by glucosinolates and isothiocyanates: requirement for at least a 6 h exposure to elicit complete induction profile.'. J Agric Food Chem, United States: 60 (22), pp. 5556-5564.doi: 10.1021/jf3011195
- .
(2012) 'The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor.'. Arch Toxicol, Germany: 86 (10), pp. 1505-1514.Full text is available at: http://epubs.surrey.ac.uk/713197/
Abstract
As the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices. In contrast, the classical Ah receptor agonist benzo[a]pyrene was a potent inducer of CYP1A1 mRNA levels, with this effect being effectively antagonized by the two isothiocyanates. In further studies, it was demonstrated that R,S-sulforaphane could both prevent the interaction of and displace already bound benzo[a]pyrene from the Ah receptor, but no concentration dependency was observed with respect to the isothiocyanate. Both erucin and R,S-sulforaphane antagonized the benzo[a]pyrene-mediated increase in the CYP1A-mediated O-deethylation of ethoxyresorufin in rat precision-cut liver slices. Of the two isomers of R,S-sulforaphane, the naturally occurring R-isomer was more effective than the S-isomer in antagonizing the activation of the Ah receptor by benzo[a]pyrene. Antagonism of the Ah receptor may be a major contributor to the established chemoprevention of aliphatic isothiocyanates.
- . (2012) 'Probabilistic orthology analysis of the ABC transporters: Implications for the development of multiple drug resistance phenotype.'. Drug Metab Dispos, 40 (7), pp. 1397-1402.
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(2012) 'Molecular Biology II: Protein function'. Elsevier Surgery, 30 (4), pp. 169-173.Full text is available at: http://epubs.surrey.ac.uk/412937/
Abstract
DNA may be viewed as the blueprint for the body, with mRNA/protein the component parts made from this blueprint. However, it is only when proteins are allowed to interact with each other and their surroundings that true biological complexity is achieved. Thus, while it is informative to study transcriptional control and mRNA transcript levels, it is equally important to assess the impact of the encoded proteins on the total cellular environment. For example, expression of a ligand-activated receptor such as the epidermal growth factor receptor is of no biological consequence if no EGF is present in the system. It is thus important to be able to study protein interactions and modification, enabling a comprehensive understanding of the biological mechanisms that underlie any particular phenotype. This article will outline the basic technologies to both visualise protein localisation and interaction between co-localised proteins. In addition, the manipulation of protein levels, both in vitro and in vivo, will be described, as this provides an important tool for the further examination of protein functionality within biological systems.
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(2012) 'Molecular biology I: Transcriptional regulation'. Elsevier Surgery, 30 (4), pp. 165-168.Full text is available at: http://epubs.surrey.ac.uk/412938/
Abstract
Whereas the DNA of the cell may be envisaged as the blueprints for a human, it is the processes of transcription and translation that act as the production line to convert these blueprints into the active protein required to produce the complex biological interactions that allow a cell to function. At its very simplest level the process of transcription is concerned with the recruitment of RNA polymerase II (Pol II) to the transcription start site of the target gene: The faster this process occurs then the more transcripts can be produced in a given amount of time and hence the more mRNA is produced to be converted to protein. This rate of Pol II recruitment can be modified through the action of a number of DNA-binding proteins (transcription factors), such as the nuclear receptors that are key sensors for the presence of therapeutic drugs within the cell In the current article we will examine the techniques available for examining the DNA:protein interactions within the regulatory regions of target genes, which result in the increased recruitment of RNA polymerase II. In addition, we will examine those techniques designed to measure the next stage, the transcription of gene coding regions to make mRNA transcripts.
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(2012) 'Characterization of Rhodamine-123 as a Tracer Dye for Use In In vitro Drug Transport Assays'. Public Library of Science PLoS One, 7 (3) Article number e33253 Full text is available at: http://epubs.surrey.ac.uk/412936/
Abstract
Fluorescent tracer dyes represent an important class of sub-cellular probes and allow the examination of cellular processes in real-time with minimal impact upon these processes. Such tracer dyes are becoming increasingly used for the examination of membrane transport processes as they are easy-to-use, cost effective probe substrates for a number of membrane protein transporters. Rhodamine 123, a member of the rhodamine family of flurone dyes, has been used to examine membrane transport by the ABCB1 gene product, MDR1. MDR1 is viewed as the archetypal drug transport protein, and is able to efflux a large number of clinically relevant drugs. In addition, ectopic activity of MDR1 has been associated with the development of multiple drug resistance phenotype, which results in a poor patient response to therapeutic intervention. It is thus important to be able to examine the potential for novel compounds to be MDR1 substrates. Given the increasing use rhodamine 123 as a tracer dye for MDR1, a full characterisation of its spectral properties in a range of in vitro assay-relevant media is warranted. Herein, we determine λmax for excitation and emission or rhodamine 123 and its metabolite rhodamine 110 in commonly used solvents and extraction buffers, demonstrating that fluorescence is highly dependent on the chemical environment: Optimal parameters are 1% (v/v) methanol in HBSS, with λex=505nm, λem=525nm. We characterise the uptake of rhodamine 123 into cells, via both passive and active processes, and demonstrate that this occurs primarily through OATP1A2-mediated facilitated transport at concentrations below 2µM, and via micelle-mediated passive diffusion above this. Finally, we quantify the intracellular sequestration and metabolism of rhodamine 123, demonstrating that these are both cell line-dependent factors that may influence the interpretation of transport assays.
- . (2012) 'Seizure control by ketogenic diet-associated medium chain fatty acids'. Neuropharmacology,
- . (2011) 'Phenethyl isothiocyanate, a naturally occurring phytochemical, is an antagonist of the aryl hydrocarbon receptor.'. Mol Nutr Food Res, Germany: 56 (3), pp. 425-434.
- .
(2011) 'Conserved valproic-acid-induced lipid droplet formation in Dictyostelium and human hepatocytes identifies structurally active compounds'. The Company of Biologists Disease Models & Mechanisms, 5, pp. 231-240.doi: 10.1242/dmm.008391Full text is available at: http://epubs.surrey.ac.uk/239122/
Abstract
Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug valproic acid (VPA). In this study, we have developed a simple model system (Dictyostelium discoideum) to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24-hour period, giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minutes of VPA treatment. Using (3)H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in human hepatocytes (Huh7 cells) labelled with [(3)H]arachidonic acid. In addition, pharmacological inhibition of beta-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium could provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds that show liver toxicology.
- .
(2011) 'The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes.'. Xenobiotica, England: 41 (7), pp. 519-529.Full text is available at: http://epubs.surrey.ac.uk/7258/
Abstract
The therapeutic class of HMG-CoA reductase inhibitors, the statins are central agents in the treatment of hypercholesterolaemia and the associated conditions of cardiovascular disease, obesity and metabolic syndrome. Although statin therapy is generally considered safe, a number of known adverse effects do occur, most commonly treatment-associated muscular pain. In vitro evidence also supports the potential for drug-drug interactions involving this class of agents, and to examine this a ligand-binding assay was used to determine the ability of six clinically used statins for their ability to directly activate the nuclear receptors pregnane X-receptor (PXR), farnesoid X-receptor (FXR) and constitutive androstane receptor (CAR), demonstrating a relative activation of PXR>FXR>CAR. Using reporter gene constructs, we demonstrated that this order of activation is mirrored at the transcriptional activation level, with PXR-mediated gene activation being pre-eminent. Finally, we described a novel regulatory loop, whereby activation of FXR by statins increases PXR reporter gene expression, potentially enhancing PXR-mediated responses. Delineating the molecular interactions of statins with nuclear receptors is an important step in understanding the full biological consequences of statin exposure. This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.
- . (2011) 'Emergence of the silicon human and network targeting drugs'. European Journal of Pharmaceutical Sciences, 46 (4), pp. 190-197.
- .
(2011) 'A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.'. Public Library of Science PLoS One, United States: 6 (2) Article number e16703 Full text is available at: http://epubs.surrey.ac.uk/2864/
Abstract
The nuclear receptor superfamily of ligand-activated transcription factors plays a central role in the regulation of cellular responses to chemical challenge. Nuclear receptors are activated by a wide range of both endogenous and exogenous chemicals, and their target genes include those involved in the metabolism and transport of the activating chemical. Such target gene activation, thus, acts to remove the stimulating xenobiotic or to maintain homeostatic levels of endogenous chemicals. Given the dual nature of this system it is important to understand how these two roles are balanced, such that xenobiotics are efficiently removed while not impacting negatively on homeostasis of endogenous chemicals. Using DNA microarray technology we have examined the transcriptome response of primary rat hepatocytes to two nuclear receptor ligands: Pregnenalone-16α-carbonitrile (PCN), a xenobiotic PXR agonist, and lithocholic acid, an endogenous mixed PXR/VDR/FXR agonist. We demonstrate that despite differences in the profile of activated nuclear receptors, transcriptome responses for these two ligands are broadly similar at lower concentrations, indicating a conserved general response. However, as concentrations of stimulating ligand rises, the transcriptome responses diverge, reflecting a need for specific responses to the two stimulating chemicals. Finally, we demonstrate a novel feed-back loop for PXR, whereby ligand-activation of PXR suppresses transcription of the PXR gene, acting to attenuate PXR protein expression levels at higher ligand concentrations. Through in silico simulation we demonstrate that this feed-back loop is an important factor to prevent hyperexpression of PXR target genes such as CYP3A and confirm these findings in vitro. This novel insight into the regulation of the PXR-mediated regulatory signal networks provides a potential mechanistic rationale for the robustness in steroid homeostasis within the cell.
- .
(2010) 'Design principles of nuclear receptor signaling: how complex networking improves signal transduction'. NATURE PUBLISHING GROUP Molecular Systems Biology, 6 Article number 446 doi: 10.1038/msb.2010.102Full text is available at: http://epubs.surrey.ac.uk/2865/
Abstract
The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands. Molecular Systems Biology 6: 446; published online 21 December 2010; doi:10.1038/msb.2010.102
- . (2010) 'Development of inducible shRNA cell models for toxicology screening'. ELSEVIER IRELAND LTD TOXICOLOGY LETTERS, 196, pp. S154-S155.
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(2009) 'Nuclear receptors: the controlling force in drug metabolism of the liver?'. TAYLOR & FRANCIS LTD XENOBIOTICA, 39 (8), pp. 597-605.Full text is available at: http://epubs.surrey.ac.uk/713425/
- . (2009) 'Molecular biology II: protein function'. Surgery, 27 (4), pp. 150-152.
- . (2009) 'Molecular biology I: transcriptional regulation'. Surgery, 27 (4), pp. 147-149.
- . (2009) 'In Silico and in Vitro Modeling of Hepatocyte Drug Transport Processes: Importance of ABCC2 Expression Levels in the Disposition of Carboxydichlorofluroscein'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 37 (2), pp. 391-399.
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(2009) 'The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1'. ACADEMIC PRESS INC ELSEVIER SCIENCE TOXICOLOGY AND APPLIED PHARMACOLOGY, 235 (1), pp. 124-134.Full text is available at: http://epubs.surrey.ac.uk/2866/
- . (2009) 'Professor George Gordon Gibson (1949-2008)'. TAYLOR & FRANCIS LTD XENOBIOTICA, 39 (8), pp. 557-557.
- . (2008) 'Can systems toxicology identify common biomarkers of non-genotoxic carcinogenesis?'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Surrey, Guildford, ENGLAND: 254 (3), pp. 164-169.
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(2008) 'Up-regulation of the glutathione S-transferase system in human liver by polycyclic aromatic hydrocarbons; comparison with rat liver and lung'. OXFORD UNIV PRESS MUTAGENESIS, 23 (4), pp. 299-308.Full text is available at: http://epubs.surrey.ac.uk/286642/
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(2008) 'Differential response of human and rat epoxide hydrolase to polycyclic aromatic hydrocarbon exposure: Studies using precision-cut tissue slices'. ELSEVIER SCIENCE BV MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 640 (1-2), pp. 153-161.Full text is available at: http://epubs.surrey.ac.uk/286641/
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(2008) 'Drug-regulated expression of Plasmodium falciparum P-glycoprotein hornologue 1: a putative role for nuclear receptors'. AMER SOC MICROBIOLOGY ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 52 (4), pp. 1438-1445.doi: 10.1128/AAC.01392-07Full text is available at: http://epubs.surrey.ac.uk/1952/
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(2008) 'Up-regulation of CYP1A/B in rat lung and liver, and human liver precision-cut slices by a series of polycyclic aromatic hydrocarbons; association with the Ah locus and importance of molecular size'. PERGAMON-ELSEVIER SCIENCE LTD TOXICOLOGY IN VITRO, 22 (1), pp. 128-145.Full text is available at: http://epubs.surrey.ac.uk/286639/
- . (2008) 'Xenobiotic and endobiotic transporters: Structure, function and regulation'. INFORMA HEALTHCARE XENOBIOTICA, 38 (7-8), pp. 654-655.
- . (2008) 'Professor George Gordon Gibson BSc, PhD, DSc, FRCPath, FBTS 1949-2008 - Obituary'. INFORMA HEALTHCARE XENOBIOTICA, 38 (7-8), pp. 653-653.
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(2007) 'The human cytochrome P450 sub-family: Transcriptional regulation, inter-individual variation and interaction networks'. ELSEVIER SCIENCE BV BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1770 (3), pp. 478-488.Full text is available at: http://epubs.surrey.ac.uk/1948/
- . (2007) 'Evaluation of the precision-cut liver and lung slice systems for the study of induction of CYP1, epoxide hydrolase and glutathione S-transferase activities'. ELSEVIER IRELAND LTD TOXICOLOGY, 231 (1), pp. 68-80.
- . (2007) 'Mixed chelate copper complex, Casiopeina IIgly (R), binds and degrades nucleic acids: A mechanism of cytotoxicity'. ELSEVIER IRELAND LTD CHEMICO-BIOLOGICAL INTERACTIONS, 165 (3), pp. 189-199.
- . (2006) 'Expressed sequence tags (ESTs) and single nucleotide polymorphisms (SNPs): What large-scale sequencing projects can tell us about ADME'. TAYLOR & FRANCIS LTD XENOBIOTICA, 36 (10-11), pp. 860-876.
- . (2006) 'Transcriptomic and phylogenetic analysis of Kpna genes: a family of nuclear import factors modulated in xenobiotic-mediated liver growth'. LIPPINCOTT WILLIAMS & WILKINS PHARMACOGENETICS AND GENOMICS, 16 (9), pp. 647-658.
- . (2006) 'Use of reporter genes to measure xenobiotic-mediated activation of CYP gene transcription.'. Methods Mol Biol, United States: 320, pp. 343-354.
- . (2006) 'Transcriptional regulation of the human pregnane-X receptor'. INFORMA HEALTHCARE DRUG METABOLISM REVIEWS, 38 (1-2), pp. 31-49.
- . (2006) 'Transcriptional regulation of the PXR gene: Identification and characterization of a functional peroxisome proliferator-activated receptor alpha binding site within the proximal promoter of PXR'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 34 (1), pp. 138-144.
- . (2005) 'In vitro assays: Crystal balls or random guesses?'. Drug Discovery Today, 10 (7), pp. 462-464.
- . (2005) 'Impact of transcription factor profile and chromatin conformation on human hepatocyte CYP3A gene expression'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 33 (2), pp. 233-242.
- . (2004) 'Interaction networks: coordinating responses to xenobiotic exposure'. ELSEVIER IRELAND LTD TOXICOLOGY, 202 (1-2), pp. 21-32.
- . (2004) 'EGF mediates monocyte chemotaxis and macrophage proliferation and EGF receptor is expressed in atherosclerotic plaques'. ELSEVIER SCI IRELAND LTD ATHEROSCLEROSIS, 176 (1), pp. 21-26.
- . (2004) 'EGF mediates monocyte chemotaxis and macrophage proliferation and EGF receptor is expressed in atherosclerotic plaques.'. Atherosclerosis, Ireland: 176 (1), pp. 21-26.
- .
(2004) 'Role of Sp1, C/EBP alpha, HNF3, and PXR in the basal- and xenobiotic-mediated regulation of the CYP3A4 gene'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 32 (5), pp. 525-535.doi: 10.1124/dmd.32.5.525
- . (2004) 'Strategies for using in vitro screens in drug metabolism'. ELSEVIER SCI LTD DRUG DISCOVERY TODAY, 9 (7) Article number PII S1359-6446(03)03019-8 , pp. 328-336.
- . (2004) 'Gene expression changes in rat liver following exposure to liver growth agents: role of Kupffer cells in xenobiotic-mediated liver growth'. PERGAMON-ELSEVIER SCIENCE LTD BIOCHEMICAL PHARMACOLOGY, 67 (1), pp. 107-118.
- . (2003) 'Sodium valproate induces apoptosis in the rat hepatoma cell line, FaO'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 192 (2-3), pp. 219-227.
- . (2003) 'Transcriptional regulation of cytochrome P4503A4 gene expression: effects of inherited mutations in the 5 '-flanking region'. TAYLOR & FRANCIS LTD XENOBIOTICA, 33 (11), pp. 1085-1095.
- . (2003) 'Lansoprazole increases testosterone metabolism and clearance in male Sprague-Dawley rats: implications for Leydig cell carcinogenesis'. ACADEMIC PRESS INC ELSEVIER SCIENCE TOXICOLOGY AND APPLIED PHARMACOLOGY, 192 (2), pp. 154-163.
- . (2003) 'Relative receptor expression is a determinant in xenobiotic-mediated CYP3A induction in rat and human cells'. TAYLOR & FRANCIS LTD XENOBIOTICA, 33 (7), pp. 703-716.
- . (2003) 'Evaluation of the toxicological relevance of CYP3A4 induction'. CURRENT DRUGS LTD CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, 6 (1), pp. 50-56.
- . (2002) 'Receptor-dependent regulation of the CYP3A4 gene'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, QUEENSLAND, AUSTRALIA: 181 Article number PII S0300-483X(02)00281-0 , pp. 199-202.
- . (2002) 'Differential gene expression in rats following subacute exposure to the anticonvulsant sodium valproate'. ACADEMIC PRESS INC ELSEVIER SCIENCE TOXICOLOGY AND APPLIED PHARMACOLOGY, 183 (2), pp. 127-134.
- . (2002) 'Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 30 (9) Article number UNSP 699/1007581 , pp. 1029-1034.
- . (2002) 'Induction of CYP3A4 gene expression by glucocorticoids occurs by a PXR-independent, as well as a PXR dependent, mechanism'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 178 (1), pp. 73-74.
- . (2002) 'The role of a liver-testis axis in the development of Leydig cell hyperplasia'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 178 (1), pp. 51-52.
- . (2002) 'Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man'. TAYLOR & FRANCIS LTD XENOBIOTICA, 32 (3), pp. 165-206.
- . (2002) 'Topics in xenobiochemistry: Receptor-dependent transcriptional activation of cytochrome P4503A genes: Induction mechanisms, species differences and interindividual variation in man'. Xenobiotica, 32 (3), pp. 165-206.
- . (2001) 'The role of liver-testis axis in the development of Leydig cell hyperplasia'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 168 (1), pp. 82-83.
- . (2001) 'Differential gene expression in xenobiotic-induced liver growth in rats'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 168 (1), pp. 102-103.
- . (2001) 'Mapping of protein-DNA interactions in the CYP3A4 proximal promoter'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 168 (1), pp. 129-130.
- . (2001) 'Investigation of host cell effects on xenobiotic induction of CYP3A'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, 168 (1), pp. 128-129.
- . (2001) 'Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 29 (11), pp. 1499-1504.
- . (2000) 'Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: Role of the glucocorticoid and pregnane X receptors'. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS DRUG METABOLISM AND DISPOSITION, 28 (5), pp. 493-496.
- . (2000) 'Predictive toxicology in drug discovery--second international conference. 10-11 November, 1999, New Orleans, LA, USA.'. IDrugs, England: 3 (3), pp. 292-294.
- . (2000) 'Control and statistical analysis of in vitro reporter gene assays'. ACADEMIC PRESS INC ANALYTICAL BIOCHEMISTRY, 278 (2), pp. 170-174.
- . (1999) 'Differential gene expression in erythromycin induced liver toxicity in rats.'. FEDERATION AMER SOC EXP BIOL FASEB JOURNAL, 13 (5), pp. A853-A853.
- . (1998) 'The coordinate regulation of DNA synthesis and suppression of apoptosis is differentially regulated by the liver growth agents, phenobarbital and methylclofenapate'. OXFORD UNIV PRESS CARCINOGENESIS, 19 (9), pp. 1521-1527.
- . (1998) 'The peroxisome proliferators are hepatocyte mitogens in chemically-defined media: glucocorticoid-induced PPAR alpha is linked to peroxisome proliferator mitogenesis'. OXFORD UNIV PRESS CARCINOGENESIS, 19 (5), pp. 925-931.
- . (1997) 'Developmental modulation of cysteine conjugate beta-lyase/glutamine transaminase K/kynurenine aminotransferase mRNA in rat brain'. MEDECINE ET HYGIENE EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, KINGS COLL LONDON, CHELSEA CAMPUS, LONDON, ENGLAND: 22 (4), pp. 335-339.
- . (1996) 'Peroxisome proliferators induce high levels of DNA synthesis in primary cultures of rat hepatocytes'. NEW YORK ACAD SCIENCES PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY AND DISEASE, ASPEN, CO: 804, pp. 745-746.
- . (1993) 'SPECIES-SPECIFIC INDUCTION OF CYTOCHROME-P-450 4A-RNAS - PCR CLONING OF PARTIAL GUINEA-PIG, HUMAN AND MOUSE CYP4A-CDNAS'. PORTLAND PRESS BIOCHEMICAL JOURNAL, 294, pp. 173-180.
Conference papers
- . (2011) 'Differential sensitivity to toxicity of statins: A comparison of liver and muscle cell lines'. TOXICOLOGY, 290 (2-3), pp. 128-129.
- . (2011) 'A systems biology approach towards understanding nuclear receptor interactions: Implications at the endocrine-xenobiotic signalling interface'. TOXICOLOGY, 290 (2-3), pp. 131-131.
- . (2011) 'Cross-species characterisation of intestinal drug transporters'. TOXICOLOGY, 290 (2-3), pp. 112-113.
- . (2011) 'Design principles of nuclear receptor signalling: How complex networking improves signal transduction'. TOXICOLOGY, 290 (2-3), pp. 131-132.
- . (2011) 'Regulation of nuclear import pathways by vitamin D signalling: Potential biological implications'. TOXICOLOGY, 290 (2-3), pp. 132-132.
- . (2010) 'The effects of time of treatment on statin muscle toxicity: Preliminary characterization of a human muscle cell line'. ELSEVIER IRELAND LTD TOXICOLOGY, Herriot Watt Univ, Edinburgh, ENGLAND: 2010 Annual Spring Meeting of the British-Toxicological-Society 278 (3), pp. 360-361.
- . (2010) 'Phylogenetic Analysis and Cross Species Characterisation of Drug Transporters in the Intestine'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Istanbul, TURKEY: 9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics(ISSX) 42, pp. 313-314.
- . (2010) 'Nuclear receptors as controlling factors in chemical metabolism: Determination of regulatory signal network crucial for co-ordinating cellular response to chemicals'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Istanbul, TURKEY: 9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics(ISSX) 42, pp. 279-280.
- . (2010) 'Examining the comparative roles of influx and efflux in determining the life cycle of chemicals within the cell'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Istanbul, TURKEY: 9th International Meeting of the International-Society-for-the-Study-of-Xenobiotics(ISSX) 42, pp. 314-315.
- . (2009) 'Transcriptional regulation of the human karyopherin alpha 2 (KPNA2) promoter by cyproterone acetate: role of the glucocorticoid receptor'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Baltimore, MD: 16th North American Regional ISSX Meeting 41, pp. 106-107.
- . (2009) 'Phylogenetic analysis of the ATP-binding cassette super-family: Implications for the development of multiple drug resistance phenotype'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Annual Congress of the British-Toxicological-Society 262 (1), pp. 12-13.
- . (2009) 'In Silico Modelling of Drug Fate and Disposition'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Annual Congress of the British-Toxicological-Society 262 (1), pp. 3-4.
- . (2009) 'Impact of transporter-mediated uptake on statin-induced gene expression in human Huh7 cells'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Annual Congress of the British-Toxicological-Society 262 (1), pp. 20-21.
- . (2009) 'Utilization of In Silico Modeling to Determine Control Coefficients for Development of Multiple Drug Resistance Phenotype in Breast Cancer Cells Exposed to the Anticancer Agent Paclitaxel'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Lisbon, PORTUGAL: 11th European Regional ISSX Meeting 41, pp. 60-60.
- . (2009) 'Response of Nuclear Import Factor Encoding Genes to Oxidative Stress'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Lisbon, PORTUGAL: 11th European Regional ISSX Meeting 41, pp. 52-52.
- . (2009) 'In Silico and In Vitro Modeling of Hepatocyte Drug Transport Processes: Control Coefficients for the Disposition of the ABCB1 Substrate Rhodamine-123'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Lisbon, PORTUGAL: 11th European Regional ISSX Meeting 41, pp. 87-88.
- . (2008) 'The human karyopherin alpha 2 promoter is responsive to oxidative stress'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Surrey, Guildford, ENGLAND: Annual Congress of the British-Toxicological-Society 253 (1-3), pp. 9-10.
- . (2008) 'Drug-regulated gene expression of Plasmodium falciparum P-glycoprotein homologue 1: a role for nuclear receptors?'. PERGAMON-ELSEVIER SCIENCE LTD INTERNATIONAL JOURNAL FOR PARASITOLOGY, Lorne, AUSTRALIA: 3rd Molecular Approaches to Malaria Meeting (MAM 2008) 38, pp. S39-S39.
- . (2007) 'A model of xenobiotic efflux via Mrp2 in sandwich cultured primary rat hepatocytes'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Surrey, Guildford, ENGLAND: Annual Congress of the British-Toxicological-Society 240 (3), pp. 158-158.
- . (2007) 'Response of nuclear import factor encoding genes to xenobiotics: Analysis of the human karyopherin alpha 2 promoter'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Surrey, Guildford, ENGLAND: Annual Congress of the British-Toxicological-Society 240 (3), pp. 179-180.
- . (2007) 'What regulates the regulator? PXR regulation by protein : protein interaction: A tale of many players'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Surrey, Guildford, ENGLAND: Annual Congress of the British-Toxicological-Society 240 (3), pp. 181-182.
- . (2007) 'Influence of metabolic stimuli on transcriptional regulation by Hepatocyte Nuclear Factor 4 alpha'. SPRINGER DIABETOLOGIA, Amsterdam, NETHERLANDS: 43rd Annual Meeting of the European-Association-for-the-Study-of-Diabetes 50, pp. S238-S239.
- . (2006) 'Evolution of the fatty acid-binding protein family: An ordered increase in gene number, correlating to more refined mechanisms of lipid processing'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Joint Congress of the British-Toxicology-Society/29th Annual Meeting of the United-Kingdom-Environmental-Mutagen-Society 226 (1), pp. 73-74.
- . (2006) 'Coordinate regulation of cellular proliferation and apoptosis in rodent liver'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Joint Congress of the British-Toxicology-Society/29th Annual Meeting of the United-Kingdom-Environmental-Mutagen-Society 226 (1), pp. 43-44.
- . (2006) 'Modulation of Six1 expression by the anti-mania agents lithium chloride and sodium valproate'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Joint Congress of the British-Toxicology-Society/29th Annual Meeting of the United-Kingdom-Environmental-Mutagen-Society 226 (1), pp. 70-71.
- . (2006) 'Species differences in the induction and activation of the pregnane X receptor (PXR)'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Coventry, ENGLAND: Joint Congress of the British-Toxicology-Society/29th Annual Meeting of the United-Kingdom-Environmental-Mutagen-Society 226 (1), pp. 42-43.
- . (2006) 'Phenol red does not affect the uptake of pravastatin by OATP2 in HuH7 cells'. TAYLOR & FRANCIS INC DRUG METABOLISM REVIEWS, Manchester, ENGLAND: 9th European Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) 38, pp. 122-123.
- . (2006) 'Modulation of six 1 expression by the anti-mania agents lithium chloride and sodium valproate'. INFORMA HEALTHCARE DRUG METABOLISM REVIEWS, Manchester, ENGLAND: 9th European Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) 38, pp. 58-58.
- . (2006) 'Transcriptomic and phylogenetic analysis of Kpna genes: A family of nuclear import factors modulated in xenobiotic-mediated liver growth'. INFORMA HEALTHCARE DRUG METABOLISM REVIEWS, Manchester, ENGLAND: 9th European Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) 38, pp. 59-59.
- . (2005) 'Species differences in xenobiotic activation of the pregnane x receptor'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Warwick, ENGLAND: 26th Spring Annual Congress of the British-Toxicology-Society 213 (3), pp. 253-254.
- . (2005) 'Coordinate regulation of cellular proliferation and apoptosis in rodent liver'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Warwick, ENGLAND: 26th Spring Annual Congress of the British-Toxicology-Society 213 (3), pp. 255-255.
- . (2005) 'Initial characterisation of the control of human Pregnane X-Receptor gene expression'. ELSEVIER IRELAND LTD TOXICOLOGY, Univ Warwick, Warwick, ENGLAND: 26th Spring Annual Congress of the British-Toxicology-Society 213 (3), pp. 254-255.
- . (2004) 'Initial characterisation of the control gene expression of the human pregnane X-receptor'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, EDINBURGH, SCOTLAND: Annual Congress of the British-Toxicology-Society 194 (3), pp. 259-260.
- . (2004) 'Cytochrome P450 3A and transcription factor mRNA expression in HuH7 cells and human liver'. ELSEVIER SCI IRELAND LTD TOXICOLOGY, EDINBURGH, SCOTLAND: Annual Congress of the British-Toxicology-Society 194 (3), pp. 265-266.
- . (2003) 'CYP3A and nuclear receptor messenger RNA expression in liver and HuH7 cells'. MARCEL DEKKER INC DRUG METABOLISM REVIEWS, DIJON, FRANCE: 8th European Meeting of the International-Society-for-the-Study-of-Xenobiotics (ISSX) 35, pp. 83-83.
- . (1996) 'Peroxisome proliferators: Species differences in response of primary hepatocyte cultures'. NEW YORK ACAD SCIENCES PEROXISOMES: BIOLOGY AND ROLE IN TOXICOLOGY AND DISEASE, ASPEN, CO: International Symposium on Peroxisomes - Biology and Role in Toxicology and Disease 804, pp. 628-635.
Teaching
Undergraduate
BMS2036 Molecular Biology and Genetics 2
BMS2047 Pharmacology 1
BMS2052 Pathology: A metabolic perspective
BMS3053 Molecular Biology and Genetics 3
BMS3055 Pharmacology 2
BMS3065 Toxicology (module organiser)
Postgraduate
Full-time courses
MSc (Toxicology)
TOXM002 Principles in Toxicology II (module organiser)
TOXM003 Tissue Specific Toxicity
TOXM007 Practical Toxicology I
TOXM009 Integrative Skills in Toxicology
MSc (Drug Discovery and Design)
CHRM010 Pharmacology and Toxicology
Msc (Medical Microbiology)
Continuing Professional Development (CPD) courses
MSc (Applied Toxicology)
MSc (Pharmaceutical Medicine and Clinical Pharmacology)
Nurse Independent/Supplementary Prescribing (V300)
Departmental Duties
Faculty-Level Duties
Faculty Research and Enterprise Committee (FRC)
Module Organiser
BMS3065 (Toxicology)
TOXM002 (Principles in Toxicology II)
University-Level Duties
REF2014 UoA Lead
Affiliations
Committee Memberships
Committee on Toxicity in Food, Consumer Products and the Environment (COT)
Medicines and Healthcare Products Regulatory Agency (MHRA) Pharmacovigilance Expert Advisory Group (MHRA PEAG)
Medicines and Healthcare Products Regulatory Agency (MHRA) Nicotine-containing products Working Group
Other Responsibilities
Associate Editor Xenobiotica
Society Memberships
British Toxicology Society (BTS)
International Society for the Study of Xenobiotics (ISSX)
