Faculty: David S. Riddick, PhD
Research Platforms: Drug Safety / Toxicology
Endocrine targets and modulators of environmental toxicant action: regulation of drug-metabolizing enzymes
Hormones are the chemical messengers of the endocrine system that regulate the body's normal functions, and they are also critical in playing adaptive roles in response to events outside the body. Some pollutants found in our environment can interfere with or disrupt the normal body functions that are controlled by hormones. These agents are referred to as "endocrine disruptors". Disruption of normal hormone pathways by environmental contaminants can contribute to several adverse or toxic effects, including cancer as well as alterations in growth, development, and reproductive function. Our goal is to understand the mechanisms by which environmental contaminants interfere with the endocrine system. In this way, we will have a clearer appreciation of why exposure to such chemicals can be detrimental and how we can prevent the adverse effects of chemical exposure. Our focus is on environmental contaminants known as aromatic hydrocarbons, of both the halogenated and polycyclic variety. This chemical class includes dioxins and polychlorinated biphenyls (PCBs), as well as PAH components of cigarette smoke and automobile exhaust. We are studying how hormones produced by the pituitary and adrenal glands control the sensitivity of an organism to the toxic effects of aromatic hydrocarbons via modulation of components of the aryl hydrocarbon receptor (AHR) response pathway and how these chemicals interfere with the normal functions of pituitary hormones. In particular, pituitary growth hormone plays a key role in controlling liver enzymes known as cytochromes P450, which are critical in the conversion of drugs, contaminants, and hormones into forms that can be eliminated from the body. Increases or decreases in cytochromes P450 are sensitive indicators of aromatic hydrocarbon exposure and we are particularly interested in the mechanisms by which exposure to AHR-activating chemicals disrupts endocrine pathways resulting in the down-regulated expression and function of hepatic P450s.
Our experimental approaches include methods for the measurement of gene expression at the mRNA, protein, and functional 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.
Crosby M and Riddick DS. Suppression of hepatic CYP3A4 expression and activity by 3-methylcholanthrene in humanized PXR-CAR-CYP3A4/3A7 mice. Drug Metab. Dispos. 2019; 47: 279-282.
Utgikar R and Riddick DS. Downregulation of cytochrome P450 2C8 by 3-methylcholanthrene in human hepatocellular carcinoma cell lines. Can. J. Physiol. Pharmacol. 2017; 95: 768-771.
- 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.
University of Toronto
Department of Pharmacology and Toxicology
Room 4318 Medical Sciences Building
1 King's College Circle
Phone:  978-0813
FAX:  978-6395