Christopher A. Reilly
Professor of Pharmacology and Toxicology, Adjunct Associate Professor of Anesthesiology and Adjunct Professor of Pediatrics
Director Center for Human Toxicology
Pulmonary Toxicology, Drug Metabolism and Pharmacokinetics, Drug Discovery
My laboratory has three areas of research: TRP ion channels in lung physiology and disease, mechanistic studies of drug metabolizing enzymes, and biological applications of mass spectrometry.
1. TRP ion channels are a family of proteins that exhibit unique functional properties and associated physiological functions. We are interested in how TRP channels regulate physiological and adverse events in the lung, with particular emphasis on the ability of these channels to elicit deleterious pulmonary inflammation and lung cell death when activated by endogenous and/or exogenous agonists; pulmonary inflammation and acute lung damage are two critical components of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and emphysema, fibrosis, and acute lung injury/ARDS. Our research is to establish roles of different members of the TRP ion channel family in the development and progression of lung injury and diseases and we have an active research program investigating receptor targets of pneumotoxicants and potential therapeutic inhibitory chemicals, the identification of specific cellular pathways that modulate deleterious and/or beneficial responses of lung cells to TRP channel agonists, and evaluation of TRP channel-dependent pathways in adverse outcomes in experimentally-induced disease states. Currently we are funded by the National Institute of Environmental Health Sciences (NIEHS) to determine how different components of polluted air adversely affect the human respiratory system via interactions with TRP channels and by local sources to study polymorphisms in TRP channels in asthmatic sensitivity to air pollutants. We are also funded by the National Institutes of General Medical Sciences in a collaborative effort with Dr. Eric W. Schmidt (Medicinal Chemistry) to discover and characterize TRP channel modulators from natural sources.
2. Xenobiotic metabolism is a collective process by which chemicals that enter our body are modified. We are interested in how human cytochrome P450 enzymes transform chemicals to pharmacologically and/or toxicologically inactive vs. toxic reactive intermediates that damage cellular macromolecules, cells, and organ systems. We have two primary areas of focus: 1) enzymatic and chemical mechanisms of oxygenation vs. dehydrogenation of substrates and analysis of modified biological macromolecules (i.e., DNA and protein) by electrophiles, particularly with respect to such processes in lung tissue; and 2) the elucidation of how variations in drug metabolism mechanisms and efficiency dictate the pharmacological and/or toxicological properties of inhaled and/or systemically-delivered therapeutic drugs. Currently research in this area is supported by grants from the National Institute of General Medical Sciences (NIGMS) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
3. Mass spectrometry is a versatile and powerful analytical technology that has revolutionized mechanistic pharmacology and toxicology studies. We use mass spectrometry to quantify a variety of substances in diverse matrices, to establish structures and metabolic origins of drug metabolites in P450 reactions, to discover unknown bioactive substances that have measurable biological activity using metabolomics-based methodology, and to identify macromolecular targets of toxic electrophiles generated by P450s. Mass spectrometric analysis is a routine approach used by our laboratory and it is supported by a variety of research grants, sub-contracts, and collaborations.
- Deering-Rice, C.E., Nguyen, N., Lu, Z., Cox, J., Shapiro, D., Romero, E.G., Mitchell, V.K., Burrell, K.L., Veranth, J.M.,Reilly, C.A. (2018) Activation of TRPV3 by Wood Smoke Particles and Roles in Pneumotoxicity. Chem. Res. Toxicol.31(5), 291-301.*Cover Article
- Lamb, J.G., Romero, E.G., Lu, Z., Marcus, S.K., Peterson, H., Veranth, J.M., Deering-Rice, C.E., and Reilly, C.A.(2017) Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells. Mol. Pharmacol. 92(6), 653-664. PMID: 29038158.
- Jaramillo, I., Sturrock, A., Kelly, K., Ghiassi, H., Jeanann, D., Deering-Rice, C., Reilly, C., Paine, R., Lighty, J. (2017) Effects of Fuel Components and Combustion Particle Physico-chemical Properties on Toxicological Responses in Lung Cells. J. Env. Sci. and Health, Part A. 53(4), 295-309.
- Deering-Rice, C., Shapiro, D., Romero, E.G., Stockmann, C., Bevans, T., Phan, Q., Stone, B., Fassl, B., Nkoy, F., Uchida, D., Ward, R., Veranth, J., Reilly, C.A. (2015) Activation of TRPA1 by Insoluble Particulate Material and Association with Asthma. Am. J. Resp. Cell Mol. Biol. 53, 893-901. PMCID: PMC4742944
- Deering-Rice, C., Stockmann, C., Romero, E.G., Shapiro, D., Stone, B., Fassl, B., Nkoy, F., Uchida, D., Ward, R., Veranth, J., Reilly, C.A. (2016) Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered TRPA1 Expression and Asthma. J. Biol. Chem. 291(48), 24866-24879. PMCID: PMC5122759.
- Shapiro, D., Deering-Rice, C.E., Romero, E.G., Hughen, R.W., Light, A.R., Veranth, J.M., and Reilly, C.A. (2013) Activation of Transient Receptor Potential Ankyrin-1 (TRPA1) by Wood Smoke Particulate Material. Chem Res. Toxicol., 26, 750-758.
- Thomas, K.C., Roberts, J.K., Deering-Rice, C.E., Dull, R.O., Lee, J., Yost, G.S., and Reilly, C.A. (2012) Contributions of TRPV1, Endovanilloids and Endoplasmic Reticulum Stress to Lung Cell Death In Vitro and Lung Injury. Am. J. Physiol-Lung Cell Mol. Physiol. 302(1), L111-119.
- Thomas, K.C., Ethirajan, M., Shahrokh, K., Sun, H., Lee, J., Cheatham III, T.E., Yost, G.S., and Reilly, C.A. (2011) Structure Activity Relationship of Capsaicin Analogues and TRPV1-Mediated Human Lung Epithelial Cell Toxicity. J. Pharm. Exp. Ther. 337(2), 400-410.
- Thomas, K.C., Sabnis, A.S., Johansen, M.E., Moos, P.J., Yost, G.S., and Reilly, C.A. (2007)TRPV1 Agonists Cause Endoplasmic Reticulum Stress and Cell Death in Human Lung Cells. J. Pharmcol. Exp. Therap. 321(3), 830-838.
- Sabnis, A.S., Shadid, M., Yost, G.S., and Reilly, C.A., (2008) Human Lung Epithelial Cells Express a Functional Cold-Sensing TRPM8 Variant. Am. J. Resp. Cell Mol.Biol.39(4),466-474
- Sabnis, A.S., Reilly, C.A., Veranth, J.M., and Yost, G.S., (2008) Increased Transcription of Cytokine Genes in Human Lung Epithelial Cells Through Activation of a TRPM8 Variant by Cold Temperatures. Am. J. Physiol-Lung Cell Mol. Physiol. 295(1), L194-200.
- Reilly, C.A., Taylor, J.L., Lanza, D.L., Carr, B.A., Crouch, D.J., and Yost, G.S. (2003) Capsaicinoids Cause Inflammation and Epithelial Cell Death Through Activation of Vanilloid Receptors. Toxicol. Sci. 73, 170-181.
- Zhang, S., Qiu, Y., Kakule, T., Lu, Z., Xu, F., Lamb, J.G., Reilly, C., Yong, Z., Sham, S.W., Wang, W., Xuan, L-J., Schmidt, E., Zhan, J., (2017) Identification of cyclic depsipeptides and their dedicated synthetase from Hapsidospora irregularis. J. Nat. Prod. 80, 363-370. PMID: 28106998.
- Rose, T.M., Reilly, C.A., Deering-Rice, C.E., Brewster, C., Brewster, C. (2014) Inhibition of FAAH, TRPV1, and COX2 by NSAID-Serotonin Conjugates. Bioorg. Med. Chem. Lett. 24, 5695-5698.
- Deering-Rice, C.E., Mitchell, V.K., Romero, E.G., Abdel Aziz, M.H., and Reilly, C.A. (2014) Drofenine: a 2-APB analog with improved selectivity for human TRPV3. Pharmacol. Res. & Perspectives. (In Press 6/3/14).
- Lin, Z., Torres, J., Ammon, M-A., Marett, L., Teichert, R., Reilly, C.A., Kwan, J.C., Hughen, R.W., Flores, M., Peraud, O., Light, A., Villaraza, A., Haygood, M.G., Concepcion, G.P., Olivera, B.M., and Schmidt, E.W. (2013) A bacterial source for mollusk pyrone polyketides. Chem. Biol., 20, 73-81.
- Lin, Z., Reilly, C.A., Antemano, R., Hughen, R.W., Marett, L., Concepcion, G.P., Haygood, M.G., Olivera, B.M., Light, A., and Schmidt, E.W. (2011) Nobilamides A-H, Long-Acting Transient receptor Potential Vanilloid-1 (TRPV1) Antagonists from Mollusk-Associated Bacteria. J. Med. Chem. 54, 3746-3755.
- Roberts, J.K., Stockmann, C., Dahl, M.J., Albertine, K.H., Egan, E., Lin, Z., Reilly, C.A., Ballard P.L., Ballard, R.A., Ward, R.M. (2016) Pharmacokinetics of Budesonide Administered with Surfactant in Premature Lambs: Implications for Neonatal Clinical Trials. Current Clin. Pharmacol. 11(1):53-61. PMID: 26416605.
- Stockmann, C., Reilly, C.A., Fassl, B., Gaedigk, R., Nkoy, F., Stone, B., Roberts, J.K., Uchida, D.A., Leeder, J.S., Sherwin, C.M.T., Spigarelli, M.G., Yost, G.S. and Ward, R.M. (2015) Effect of CYP3A5*3 on Asthma Control among Children Treated with Inhaled Beclomethasone Dipropionate. J. Allergy. Clin. Immunol. 136(2), 505-507.
- Moore, C.D., Roberts, J.K., Orton, C.R., Murai, T., Fidler, T.P., Reilly, C.A., Ward, R.M., and Yost, G.S. (2013) Metabolic Pathways of Inhaled Glucocorticoids by the CYP3A Enzymes. Drug Metab. Disp., 41(2), 379-389.
- Roberts, J.K., Moore, C.D., Ward, R.M., Yost, G.S., and Reilly, C.A. (2013) Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes. J. Pharmacol. Exp. Therap., 345, 308-316.
- Roberts, J.K., Moore, C.D., Romero, E.G., Ward, R.M., Yost, G.S., and Reilly, C.A. (2013) Regulation of CYP3A Genes by Glucocorticoids in Human Lung Cells. F1000 Research 2:173, 1-10. (Featured article, 9/23/13-9/30/13)
- Stockmann, C., Fassl, B., Gaedigk, R., Nkoy, F, Uchida, D., Monson, S., Reilly, C.A., Leeder, J.S., Yost, G.S., Ward, R.M., (2013) Fluticasone Propionate Pharmacogenetics: CYP3A4*22 Polymorphism Improves Pediatric Asthma Control. J. Pediatrics. 162, 1222-1227.
- Moore, C.D., Reilly, C.A., Yost, G.S. (2010) CYP3A4-Mediated Dehydrogenation Versus Oxygenation of Raloxifene. Biochemistry 49, 4466-4475.
- Murai, T, Reilly, C.A., Ward, R.M., and Yost, G.S. (2010) Fluticasone Propionate, an Inhaled Glucocorticoid, is a Potent Inactivator of CYP3A5, the Predominant Pulmonary P450 Enzyme. Chem. Res. Toxicol. 23, 1356-1364.
- Kartha, J.S., Skordos, K.W., Sun, H., Hall, C., Easterwood, L.M., Reilly, C.A., C.A., Johnson, E.F., and Yost, G.S.(2008) Single Mutations Change CYP2F3 From a Dehydrogenase of 3-Methylindole to an Oxygenase. Biochemistry 47(37), 9750-9770.
- Sun H., Ehlhardt, W.J., Kulanthaivel, P., Lanza, D.L., Reilly, C.A., and Yost G.S. (2007) Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel Aromatase Process. J. Pharmacol. Exp. Therap. 322(2), 843-851.
- Reilly, C.A. and Yost, G.S. (2005) Structural and Enzymatic Parameters that Determine Alkyl Dehydrogenation/Hydroxylation of Capsaicinoids by P450 Enzymes. Drug Metab. Disp., 33(4),530-6.
- Simmonds, A.C., Reilly, C.A., Baldwin, R.M., Ghanayem, B.I., Lanza, D.L., Yost, G.S., Collins, K.S., and Forkert, P.G. (2004) Bioactivation of 1,1-dichloroethylene to its epoxide by CYP2E1 and CYP2F enzymes. Drug Metab. Disp. 32(9), 1032-1039.
- Reilly, C.A., Ehlhardt, W.J., Jackson, D.A., Kulanthaivel P., Mutlib, A.E., Espina, R.J., Moody D.E, Crouch, D.J., and Yost, G.S. (2003) Metabolism of Capsaicin by Cytochrome P450 Produces Novel Dehydrogenated Metabolites and Decreases Cytotoxicity to Lung and Liver Cells. Chem. Res. Toxicol. 16(3), 336-349.
- Linakis, M.W., Stockman, C., Campbell, S.C., Williams, R.V., Burch, P.T., Lambert, L.M., Sherwin, C.M., Reilly, C.A., and Spigarelli, M.G. (2015) Quantitative Assay Validation for Oxandrolone in Human Plasma Using LC/MS/MS. J. Analyt. Toxicol. 39(7):526-31.
- Phillips, J.D., Bergonia, H., Reilly, C.A., Franklin, M.R., and Kushner, J.P. (2006) A Porphomethene Inhibitor of Uroporphyrinogen Decarboxylase Causes Porphyria Cutanea Tarda. Proc. Nat. Acad. Sci., 104(12), 5079-5084.
- Reilly, C.A. and Crouch, D.J. (2003) Analysis of the Nutritional Supplement 1AD, Its Metabolites, and Related Endogenous Hormones in Biological Matrices Using Liquid Chromatography-Tandem Mass Spectrometry. J. Analyt. Toxicol. 28, 1-10.
- Pershing, L.K., Reilly, C.A., and Crouch, D.J. (2004) Effects Of Vehicle On The Uptake And Elimination Kinetics Of Capsaicinoids In Human Skin In Vivo. Toxicol. Appl. Pharmacol. 200, 73-81.
- Welch, K.D., Reilly, C.A., and Aust, S.D. (2002) The Role of Cysteine Residues in the Oxidation of Ferritin. Free Rad. Biol. Med. 33, 399-408.
- Reilly, C.A., Crouch, D.J., Yost, G.S., and Fatah, A.A. (2002) Determination of Capsaicin, Nonivamide, and Dihydrocapsaicin in Blood and Tissue by Liquid Chromatography-Tandem Mass Spectrometry. J. Analyt. Toxicol. 26, 313-319.
- Reilly, C.A., Crouch, D.J., Fatah, A.A., and Yost, G.S. (2001) Determination of Capsaicin, Dihydrocapsaicin, and Nonivamide in Self-Defense Weapons by Liquid Chromatography-Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry. J. Chromatogr. A 912, 259-267.