Waxman D.J., Chang T.K.H. (2020) Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. In: Offermanns S., Rosenthal W. (eds) Encyclopedia of Molecular Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-030-21573-6_234-1
Erickson SL, Alston L, Nieves K, Chang TKH, Mani S, Flannigan KL, Hirota SA. The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered by C difficile toxins. FASEB J. 2020 Feb;34(2):2198-2212. doi: 10.1096/fj.201902083RR. Epub 2019 Dec 17. PMID: 31907988; PMCID: PMC7027580.
Hudson G, Flannigan KL, Venu VKP, Alston L, Sandall CF, MacDonald JA, Muruve DA, Chang TKH, Mani S, Hirota SA. Pregnane X Receptor Activation Triggers Rapid ATP Release in Primed Macrophages That Mediates NLRP3 Inflammasome Activation. J Pharmacol Exp Ther. 2019 Jul;370(1):44-53. doi: 10.1124/jpet.118.255679. Epub 2019 Apr 19. PMID: 31004077; PMCID: PMC6542184.
Sharma D, Turkistani AA, Chang W, Hu C, Xu Z, Chang TKH. Negative Regulation of Human Pregnane X Receptor by MicroRNA-18a-5p: Evidence for Suppression of MicroRNA-18a-5p Expression by Rifampin and Rilpivirine. Mol Pharmacol. 2017 Jul;92(1):48-56. doi: 10.1124/mol.116.107003. Epub 2017 Apr 13. PMID: 28408657.
Lau AJ, Politi R, Yang G, Chang TK. Cell-based and in silico evidence against quercetin and structurally-related flavonols as activators of vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:59-67. doi: 10.1016/j.jsbmb.2016.03.039. Epub 2016 Apr 1. PMID: 27041117.
"Senior Scholar Award". Chang TKH. Michael Smith Foundation for Health Research. 2007-2012
"Killam Faculty Research Fellowship". Chang TKH. Izaak Walton Killam Trust. 2006.
"Distinguished University Scholar Award". Chang TKH. The University of British Columbia. 2002.
"New Investigator Award". Chang TKH. Burroughs Wellcome Fund (U.S.A.). 1998.
"Research Career Award". Chang TKH. Canadian Institute of Health Research and Rx&D Health Research Foundation. 1997-2002.
"Research Scholar Award". Chang TKH. British Columbia Health Research Foundation. 1997-2001.
Dr. Thomas K. H. Chang completed a bachelor of science and a doctor of philosophy in pharmaceutical sciences at UBC. He pursued his postdoctoral studies in the Division of Cancer Pharmacology at the Dana-Farber Cancer Institute and the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. Dr. Chang also completed the faculty certificate program on Teaching and Learning in Higher Education at UBC.
Currently, Dr. Chang is Professor and Associate Dean, Graduate and Postdoctoral Studies and a UBC Distinguished University Scholar.
Nuclear receptors are evolutionarily-related DNA-binding transcription factors that regulate the expression of a broad array of genes involved in various biological processes. There are 48 known members in the superfamily of nuclear receptors in the human genome. Of particular interest to Dr. Chang’s laboratory are nuclear receptors that govern the actions of genes (e.g. transporters such as P-glycoprotein and drug-metabolizing enzymes such as cytochromes P450), and regulate the transport, bioactivation and detoxification of xenobiotics (e.g. drugs, environmental chemicals) and endogenous substances (e.g. steroid hormones, vitamins, bile acids). These nuclear receptors include constitutive androstane receptor (CAR) and pregnane X receptor (PXR). The overall goal of Dr. Chang’s research program is to enhance our understanding of the molecular and cellular determinants that regulate the transport, bioactivation and detoxification of drugs, and how they affect inter-individual differences in drug action. Dr. Chang’s research program is supported by the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research.
Chemical Biology and Pharmacology of Nuclear Receptors
Nuclear receptors such as constitutive androstane receptor and pregnane X receptor are potential therapeutic targets for various human diseases. Thus, it is important to identify chemical modulators of these receptors. Studies are underway that focus on natural products and synthetic drugs. This will pave the way for future drug development efforts to find selective, potent and effective modulators. Other studies include elucidating the cellular and molecular mechanisms by which drugs and other chemicals activate constitutive androstane receptor and pregnane X receptor, and identifying the various factors that regulate the expression and function of these nuclear receptors.
Functional Analysis of Splice Variants of Nuclear Receptors
Alternative splicing of a gene results in the formation of multiple protein isoforms with varying amino acid sequence. The splice variants may have different regulation, function and tissue distribution when compared with the wild-type isoform. There are many splice variants of the human constitutive androstane receptor, several of which are expressed predominantly in the liver. Various studies are ongoing to investigate the functionality of naturally occurring splice variants of the human constitutive androstane receptor (e.g. hCAR-SV23, hCAR-SV24).