James Hammond
Dr James Hammond 
Professor, Director of Undergraduate Education
Education:
BSc (Hons), Physiology & Pharmacology, University of Western Ontario, 1979
PhD, Pharmacology, University of Alberta, 1983
Contact Information:
Awards
Inaugural Fellow of the Canadian Society of Pharmacology and Therapeutics
Teaching: PMCOL 337
Research:
Pharmacological, functional and molecular characterization of the membrane transport systems responsible for the cellular uptake and release of endogenous nucleosides and nucleobases and their anticancer/antiviral analogues.
Research Interests / Laboratory Techniques
Research Area: Multiple subtypes of nucleoside/nucleobase transporters have been identified by both functional and molecular approaches. Two broad gene families have been identified: 1) Equilibrative nucleoside transporters (SLC29A; ENT) that operate by facilitated diffusion and 2) Concentrative sodium/nucleoside co-transporters (SLC28A; CNT). Seven of these transporters have been cloned from a number of mammalian (including human) tissues (ENT1, ENT2, ENT3, ENT4, CNT1, CNT2, CNT3). We cloned the canine ENT1 and the mouse ENT1 and ENT2, as well as two novel splice variants of the mouse ENT1 transporter. The physiological and pharmacological significance of the multiple transporter subtypes/variants has yet to be fully established. Nucleoside transporter heterogeneity impacts significantly on the actions of many drugs that act through adenosine receptors or by modifying cellular nucleoside metabolism. This has particular relevance to the clinical activities of the cytotoxic nucleoside analogues used in cancer chemotherapy (e.g. cytosine arabinoside, gemcitabine, 2-chlorodeoxyadenosine), as well as drugs that modify vascular function via modulation of the adenosine signalling pathways. In addition, a novel nucleobase transporter has been identified (SLC43A3) which we have recently established as playing an important role in mediating the cellular uptake and cytotoxicity of nucleobase analogue drugs such as the 6-thiopurines used in cancer therapy and for the treatment of intestinal bowel disorders such as Crohn's Disease.
Current research projects:
1) The analysis of the protein structural elements involved in the interaction of drugs and substrates with the multiple subtypes and isoforms of equilibrative nucleoside and nucleobase transporters. Studies involve the generation of point mutants (site-directed mutagenesis) and their expression in transporter-deficient mammalian cell lines using CRISPR-Cas9 techniques. Nucleoside transport activity of the native and recombinant proteins is measured directly by the cellular accumulation of radiolabelled substrates and indirectly using specific probes for the proteins associated with the transporter (Funded by NSERC)
2) The role of protein phosphorylation in the activity and membrane turnover of the purine transporters, Investigation of mechanisms to modify transporter expression/activity by modifying regulatory pathways to enhance therapies with nucleoside/nucleobase analogue drugs. This work also includes examination of the impact of transporter dimerization and intracellular protein interactions on transporter function (Funded by NSERC and CIHR).
3) Analysis of the role of variations in the expression of SLC43A3 in the therapeutic efficacy and side-effect profile of 6-mercaptopurine when used to treat acute lymphoblastic leukemia. This work involves translational studies focused on SLC43A3 variability and function in leukemia patient samples, as well as analysis of recombinant cell lines and in vivo mouse models (Funded by CIHR).
Selected Recent Publications
Best, K.A., Bone, D.B., Vilas, G., Gros, R., Hammond, J.R. (2018) Changes in aortic reactivity associated with the loss of equilibrative nucleoside transporter 1 (ENT1) in mice. PLoS One 13(11): e0207198
Veras, M.A., Tenn, N.A., Kuljanin, M. Lajoie, G.A., Hammond, J.R., Dixon, S.J., Seguin, C.A. (2019) Loss of ENT1 increases cell proliferation in the annulus fibrosus of the intervertebral disc. Cell. Physiol., 234: 13705-13719.
Ruel, N.M., Nguyen, K.H., Vilas, G., Hammond, J.R. (2019) Characterization of 6-mercaptopurine transport by the SLC43A3-encoded nucleobase transporter. Molec Pharmacol., 95: 584-596.
Tandio, D., Vilas, G., Hammond, J.R. (2019) Bidirectional transport of 2-chloroadenosine by equilibrative nucleoside transporter 4 (hENT4): Evidence for allosteric kinetics at acidic pH. Scientific Reports 9(1): 13555.
Wei, R., Gust, S.L, Tandio, D., Maheux, A., Nguyen, K.H, Wang, J., Bourque, S.*, Plane, F.*, Hammond, J.R.* (2020) Changes in vascular regulation of mouse mesenteric resistance vessels by nitric oxide and adenosine in response to genetic deletion of Slc29a4 (ENT4). Physiological Reports 8:e14395.
Ruel N.M., Nguyen K.H., Kim C.S., Andrade L.P.S., Hammond J.R. (2022) Impact of SLC43A3/ENBT1 expression and function on 6-mercaptopurine transport and cytotoxicity in human acute lymphoblastic leukemia cells. J Pharmacol Exp Ther. 2022 382(3):335-345.
Ii H, Warraich S, Tenn N, Quinonez D, Holdsworth DW, Hammond JR, Dixon SJ and Séguin CA. (2016) Disruption of biomineralization pathways in spinal tissues of a mouse model of diffuse idiopathic skeletal hyperostosis. Bone 90:37-49. PMID: 27237608.
Hughes SJ, Cravetchi X, Vilas G and Hammond JR. (2015) Adenosine A1 receptor activation modulates human equilibrative nucleoside transporter 1 (hENT1) activity via PKC-mediated phosphorylation of serine-281. Cell Signal 27(5):1008-18. PMID: 25725289.
Bone DB, Antic M, Quinonez D, Hammond JR. (2015) Hypoxanthine uptake by skeletal muscle microvascular endothelial cells from equilibrative nucleoside transporter 1 (ENT1)-null mice: effect of oxidative stress. Microvasc Res 98:16-22. PMID: 25448155
Bone DB, Antic M, Vilas G and Hammond JR. (2014) Oxidative stress modulates nucleobase transport in microvascular endothelial cells. Microvasc Res 95C:68-75. PMID: 24976360.
Warraich S, Bone DB, Quinonez D, Ii H, Choi DS, Holdsworth DW, Drangova M, Dixon SJ, Seguin CA and Hammond JR. (2013) Loss of equilibrative nucleoside transporter 1 (ENT1) in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. J Bone Miner Res 28(5):1135-49. PMID: 23184610.
Park JS and Hammond JR. (2012) Cysteine Residues in the TM9-TM11 Region of the Human Equilibrative Nucleoside Transporter Subtype 1 Play an Important Role in Inhibitor Binding and Translocation Function. Mol Pharmacol 82(5):784-94. PMID: 22837314.
Park JS, Hughes SJ, Cunningham FK and Hammond JR. (2011) Identification of Cysteines Involved in the Effects of Methanethiosulfonate Reagents on Human Equilibrative Nucleoside Transporter 1. Mol Pharmacol 80(4):735-46. PMID: 21791574.
Bone DB, Choi DS, Coe IR and Hammond JR. (2010) Nucleoside/nucleobase transport and metabolism by microvascular endothelial cells isolated from ENT1 -/- mice. Am J Physiol Heart Circ Physiol 299 (3):H847-H856. PMID: 20543083.
Robillard KR, Bone DB, Park JS and Hammond JR. (2008) Characterization of mENT1Delta11, a novel alternative splice variant of the mouse equilibrative nucleoside transporter 1. Mol Pharmacol 74 (1):264-273. PMID: 18413666.
Bone DB and Hammond JR. (2007) Nucleoside and nucleobase transporters of primary human cardiac microvascular endothelial cells: Characterization of a novel nucleobase transporter. Am J Physiol Heart Circ Physiol 293:H3325-H3332. PMID: 17921321.
Nicholas Ruel (ruel@ualberta.ca)