Toxicology, Drug Metabolism and Animal Models of Disease
To cause serious adverse effects, many drugs and environmental chemicals require metabolism or “bioactivation” to a highly reactive intermediate, such as an electrophile or free radical, that irreversibly binds to or oxidatively damages essential cellular macromolecules like DNA, proteins and lipids. This macromolecular damage, if not repaired, results in abnormal cellular function or cellular death. We are particularly interested in free radical intermediates that initiate the formation of reactive oxygen species (ROS), which may exert their adverse effects by oxidatively damaging cellular macromolecules and/or altering signal transduction pathways. ROS may contribute not only to important drug toxicities, but also to a spectrum of diseases including cancer and neurodegenerative diseases.
Our research is directed towards understanding the molecular and biochemical mechanisms resulting in such pathological sequelae, and the environmental and genetic determinants of individual susceptibility. A number of spontaneous and drug-induced diseases are explored in human subjects and in animal models, including liver and neurodegenerative diseases, birth defects, developmental deficits in CNS function and cancer. Relevant genes, proteins/enzymes and molecular target damage are assessed using a combination of chemical, biochemical and molecular biological techniques. To optimize interpretation of the results, in vivo studies are combined with a variety of in vitro approaches, including embryo and cell culture, as well as studies in subcellular fractions and at the molecular level.
Our current research is focused in several often complementary areas. The first involves the elucidation of mechanisms of drug-induced embryonic death, birth defects and postnatal functional deficits, and identification of those mothers and unborn children who are at high risk. The second area focuses upon embryonic conditions potentially contributing to the subsequent risk for cancer in childhood or later in life. A third area involves the contribution of ROS in neurodegenerative diseases, and the role of oxidative and antioxidative pathways determining risk. Complementary to these areas are studies to determine the role of oxidative DNA damage and repair in disease and drug toxicity.
Knowledge gained in such studies facilitates the identification of toxicologically predisposed humans, the development of strategies to minimize unwarranted drug toxicity, and an understanding of disease mechanisms, risk factors and novel treatments.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street
Toronto, Ontario, M5S 3M2