John P. Harrelson, PhD
Dr. Harrelson teaches medicinal chemistry, drug metabolism, toxicology, and pharmacogenomics/genetics of ADME enzymes during the first-year pharmacy curriculum.
PHRM 562 | Pharmacokinetics and Pharmacodynamics
PHRM 565 | Central Nervous System II
PHRM 570 | PCR III Medicinal Chemistry of Cardiovascular, Pulmonary, and Renal Drugs
PHRM 583 | Immunology and Toxicology
2005 | Doctor of Philosophy, Medicinal Chemistry, University of Washington, Seattle, WA
1994 | Bachelor of Science, Chemistry, Gonzaga University, Spokane, WA
Areas of Research & Specialization
The broad research emphasis in this lab is the investigation of factors that influence interpatient variability in drug toxicity and response to therapy. The work investigates several areas including reactive metabolite formation, drug-drug /drug-diet interactions, structure-toxicity/ADME relationships, idiosyncratic adverse drug reactions, genetic polymorphisms, and structure-function studies of drug metabolizing enzymes.
This research requires an interdisciplinary and collaborative approach and therefore a variety of biophysical methods and bioanalytical tools are used to carry out this work. These include HPLC-fluorescence, mass spectrometry, mechanism-based inhibition, kinetic isotope effects, in vitro-in vivo extrapolation (IVIVE), molecular modeling, protein expression/purification, and metabolite synthesis.
Currently the lab's primary focus is on cytochrome P450 2A6 (CYP2A6). CYP2A6 is the major human nicotine-metabolizing enzyme, and exhibits profound genetic variability leading to diversity in nicotine clearance within the human population. We are conducting structure-function studies of CYP2A6 using plant metabolites (i.e., phenylpropanoids and terpenoids) present in the diet (e.g., cinnamon aldehyde from cinnamon oil) and are investigating the modulation of CYP2A6 and genetic variants by these compounds. This work has potential to provide new mechanistic insights in the areas of smoking cessation, structure-toxicity relationships, cancer chemoprevention, and drug-diet interactions involving CYP2A6.
(* indicates Pacific University student researcher)
Harrelson JP and Lee MW. Expanding the view of breast cancer metabolism: Promising molecular targets and therapeutic opportunities, Pharmacology & Therapeutics (2016) doi: 10.1016/j.pharmthera.2016.07.014. [Epub ahead of print], http://www.sciencedirect.com/science/article/pii/S0163725816301395
Chan J, Oshiro T*, Thomas S*, Higa A*, Black S*, Todorovic A, Elbarbry F, and Harrelson JP. Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole, Drug Metabolism and Disposition, 44 (2016), 534-543. http://dmd.aspetjournals.org/content/44/4/534.abstract
Childers WK*, Harrelson JP. Allosteric Modulation of Substrate Motion in Cytochrome P450 3A4-mediated Xylene Oxidation, Biochemistry, 53 (2014), 1018-1028.
Harrelson, J.P., Stamper, B.D., Chapman, J.D., Goodlett, D.R., and Nelson, S.D. Covalent Modification and Time-Dependent Inhibition of Human CYP2E1 by the meta-Isomer of Acetaminophen, Drug Metabolism and Disposition 40 (2012) 1460-1465.
Mao, J., Mohutsky, M.A., Harrelson, J.P., Wrighton, S.A., and Hall, S.D. Predictions of cytochrome P450-mediated drug-drug interactions using cryopreserved human hepatocytes: comparison of plasma and protein-free media incubation conditions, Drug Metabolism and Disposition 40 (2012) 706-716.
Mao, J., Mohutsky, M.A., Harrelson, J.P., Wrighton, S.A., and Hall, S.D. Prediction of CYP3A-mediated drug-drug interactions using human hepatocytes suspended in human plasma, Drug Metabolism and Disposition 39 (2011) 591-602.
Harrelson, J.P., Atkins, W.M., and Nelson, S.D. Multiple-ligand binding in CYP2A6: probing mechanisms of cytochrome P450 cooperativity by assessing substrate dynamics, Biochemistry47 (2008), 2978-2988.
(* indicates Pacific University student researcher)
Black S*, Chan J, and Harrelson JP. Evidence for Heme Degradation in the Mechanism-Based Inhibition of CYP2A6-Mediated Letrozole and Coumarin Metabolism by trans-Cinnamic Aldehyde, poster presentation at the American Association of Pharmaceutical Scientists Rocky Mountain Discussion Group 2nd Annual Meeting, Missoula, MT, August 2014.
Black S*, Thurman B, and Harrelson JP. CYP3A4-Mediated Letrozole Metabolism Is Activated by Ketoconazole and Dependent on Substrate Concentration, poster presentation at the American Association of Pharmaceutical Scientists Rocky Mountain Discussion Group 2nd Annual Meeting, Missoula, MT, August 2014.
Black S*, Thurman B, and Harrelson JP. Activation of CYP3A4 Mediated Letrozole Metabolism by Ketoconazole, poster presentation at Experimental Biology 2014 (ASPET Drug Metabolism Division), San Diego, CA, April 2014.
Todorovic, A., Oshiro, T.*, Chan, J.M., and Harrelson, J.P. Modulation of CYP2A6-mediated Letrozole Metabolism by trans-Cinnamic Aldehyde, 18th International Conference on Cytochrome P450 Biochemistry, Biophysics and Biotechnology, Seattle, WA, June, 2013.
Thomas, S.*, Chan, J., and Harrelson, J.P. Estimation of Nicotine-Diet Interactions Due to Time Dependent Inhibition of CYP2A6 by trans-Cinnamic Aldehyde, Gordon Research Conference On Drug Metabolism, Plymouth, NH, July, 2011.
Harrelson, J.P., Kaspera, R., Bali, S.*, Nishikawa, R.*, and Chan, J. Trans-Cinnamic Aldehyde is a Time-Dependent Inhibitor of Human CYP2A6, 13th International Drug-Drug Interaction Conference and 8th International Conference on Early Toxicity Screening, Seattle, WA, June, 2010.
Harrelson, J.P. and Neslon, S.D. The meta Isomer of Acetaminophen is a Time Dependent Inhibitor of Human CYP2E1, International Society for the Study of Xenobiotics (ISSX) workshop on Genetic Polymorphisms in Drug Disposition, Indianapolis, IN, April, 2010.
Buhler, A.V., Arendt, C.S., Elbarbry, F., Fortner, J., Harrelson, J.P., Jackson, K.C., Jordan, J.M., Marcus, K., Millard, M.E., Pokala, V. Cross-Discipline Case Studies Integrate Basic Science and Clinical Skills for First-Year Students in Modified-Block Curriculum, American Association of Colleges of Pharmacy Annual Meeting, Boston, MA, July, 2009.
Childers, W.K.* and Harrelson, J.P. Mechanistic Investigation of CYP3A4 Allosterism by Assessing Ligand Dynamics, International Society for the Study of Xenobiotics (ISSX) Annual Meeting, San Diego, CA, October, 2008.
Childers, W.K.* and Harrelson, J.P. Allosteric Effects and Multiple Substrate Binding, Murdoch Undergraduate Research Conference, Willamette University, Salem, OR, November, 2007.
Harrelson, J.P., Atkins, W.M., and Nelson, S.D. Substrate Dynamics and Multiple-Ligand Binding in CYP2A6: Investigating Mechanisms of P450 Allosterism Using Deuterium Isotope Effects, Gordon Research Conference On Drug Metabolism, Plymouth, NH, July 2006.