Faculty: David S. Riddick, PhD
General Research Areas: Drug Metabolism/Molecular Pharmacology & Toxicology/Cancer
Regulation of Drug-Metabolizing Enzymes: Implications for Toxicology and Cancer Chemotherapy
The cytochromes P450 (CYP) constitute a superfamily of hemoproteins, many of which are involved in the metabolism of xenobiotics and endogenous substances. A central goal of our laboratory is the elucidation of the molecular mechanisms by which xenobiotics alter the expression of genes encoding specific CYP enzymes in liver. We are particularly interested in the mechanisms by which antineoplastic drugs (e.g. anthracyclines) and environmental toxicants of the aromatic hydrocarbon class (e.g. dioxins, PCBs, PAHs) cause both induction and suppression of specific hepatic CYPs, and the role that endogenous hormones play in these processes. We focus mainly on transcriptional mechanisms of gene regulation. Many of the toxic and adaptive responses to aromatic hydrocarbon exposure are mediated by the aromatic hydrocarbon receptor (AHR) and a current focus involves the ability of these chemicals to act as endocrine disruptors. In particular, we are characterizing endogenous hormones as both targets and modulators of aromatic hydrocarbon action. Our experimental approaches include methods for the measurement of CYP regulation at the DNA, mRNA, protein, and catalytic function levels, as well as pharmacological and biochemical methods for dissecting the impact of xenobiotics on endocrine circuits and signal transduction pathways. Our work includes investigations carried out with whole animals (rat and mouse), cultured cells, and in vitro biochemical and molecular systems. We are attempting to elucidate the molecular basis for alterations in the metabolism of drugs, toxicants, and hormones that occur following exposure to aromatic hydrocarbons and during cancer chemotherapy.
We are also interested in the role that drug-metabolizing enzymes play in making human cancer cells resistant to chemotherapeutic agents (e.g. anthracyclines). The glutathione S-transferases (GST) are phase II conjugation enzymes that play key roles in detoxification. Overexpression of GST enzymes is a mechanism by which tumors may become resistant to chemotherapeutic agents. We assess the contributions that various GST enzymes make to the resistance of human breast and colon cancer cell lines and we are interested in whether these cells can be sensitized to the cytotoxic effects of antineoplastics by selectively inhibiting GST enzymes. We also study the role of CYP enzymes (and its partner, NADPH-CYP reductase) in the bioactivation of selected antineoplastic agents. We are interested in whether overexpression of these enzymes in human cancer cell lines can sensitize the cells to the cytotoxic effects of chemotherapeutic drugs.
Hunter SR, Vonk A, Mullen Grey AK and Riddick DS. Role of glucocorticoid receptor and pregnane X receptor in dexamethasone induction of rat hepatic aryl hydrocarbon receptor nuclear translocator and NADPH-cytochrome P450 oxidoreductase. Drug Metab. Dispos. 2017; 45: 118-129.
Lee C, Mullen Grey AK, and Riddick DS. Loss of aryl hydrocarbon receptor protein in adrenalectomized rats does not involve altered levels of the receptor's cytoplasmic chaperones. Can. J. Physiol. Pharmacol. 2013; 91: 1154-1157.
Lee C, Ding X, and Riddick DS. Downregulation of mouse hepatic CYP3A protein by 3-methylcholanthrene does not require cytochrome P450-dependent metabolism. Drug Metab. Dispos. 2013; 41: 1782-1786.
Lee C, Ding X, and Riddick DS. The role of cytochrome P450-dependent metabolism in the regulation of mouse hepatic growth hormone signaling components and target genes by 3-methylcholanthrene. Drug Metab. Dispos. 2013; 41: 457-465.
Wu AML, Dalvi P, Lu X, Yang M, Riddick DS, Matthews J, Clevenger CV, Ross DD, Harper PA, and Ito S. Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells. Mol. Pharmacol. 2013; 83: 377-388.
Riddick DS, Ding X, Wolf CR, Porter TD, Pandey AV, Zhang QY, Gu J, Finn RD, Ronseaux S, McLaughlin LA, Henderson CJ, Zou L, and Flück CE. NADPH-Cytochrome P450 reductase: roles in physiology, pharmacology, and toxicology. Drug Metab. Dispos. 2013; 41: 12-23.
Lee C and Riddick DS. Aryl hydrocarbon receptor-dependence of dioxin's effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components. Can. J. Physiol. Pharmacol. 2012; 90: 1354-1363.
Mullen Grey AK and Riddick DS. The aryl hydrocarbon receptor pathway and the response to 3-methylcholanthrene are altered in the liver of adrenalectomized rats. Drug Metab. Dispos. 2011; 39: 83-91.
Mullen Grey AK and Riddick DS. Glucocorticoid and adrenalectomy effects on the rat aryl hydrocarbon receptor pathway depend on the dosing regimen and post-surgical time. Chemico-Biol. Interact. 2009; 182: 148-158.
Sawaya RM and Riddick DS. Cytochrome P450 2C11 5'-flanking region and promoter mediate in vivo suppression by 3-methylcholanthrene. Drug Metab. Dispos. 2008; 36: 1803-1811.
Sawaya RM and Riddick DS. Cytochrome P450 2C11 5'-flanking region and promoter: regulation by aromatic hydrocarbons in vitro. Toxicology. 2008; 248: 104-112.
Bielefeld KA, Lee C, and Riddick DS. Regulation of aryl hydrocarbon receptor expression and function by glucocorticoids in mouse hepatoma cells. Drug Metab. Dispos. 2008; 36:543-551.
Riddick DS. Drug biotransformation. In: Principles of Medical Pharmacology, 7th Edition (Kalant H, Grant DM, Mitchell J, eds) Elsevier Canada, Toronto. 2007; pp. 34-49.
Lee C, Hutson JR, Tzau VK-F, and Riddick DS. Regulation of constitutive mouse hepatic cytochromes P450 and growth hormone signaling components by 3-methylcholanthrene. Drug Metab. Dispos. 2006; 34:1530-1538.
Harper PA, Riddick DS, and Okey AB. Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. Biochem. Pharmacol. 2006; 72: 267-279.
University of Toronto
Department of Pharmacology and Toxicology
Room 4318 Medical Sciences Building
1 King's College Circle
Phone:  978-0813
FAX:  978-6395