Faculty: Peter J. O'Brien, PhD
General Research Area: Biochemical and Molecular Toxicology
Mechanisms of Drug-Induced Cytotoxicity and Its Prevention
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Most drugs have a limited dosage as a result of toxic side effects that develop following chronic use. Toxicity also occurs when higher doses are administered accidentally or deliberately. Drugs chosen for their toxicity towards tumor cells can also cause toxicity towards normal tissues. We are exploring ways of decreasing the toxicity of drugs or naturopathic agents. These methods include the use of less toxic drug analogues, antidotes, improving the nutritional status of the patient and targeting of the drug to the tissue that requires therapy. The molecular mechanisms by which some natural products or drugs prevent the development of cancer (chemoprevention) are also being investigated.
The biochemical research techniques used include the monitoring of changes in biomolecules and cellular metabolism when drugs are administered in vivo, perfused intact organs, or incubated with intact cells, cultured cells or subcellular fractions. Drugs currently being studied include analgesics, anaesthetics, anticancer quinone/phenolics, antidiabetic and nonsteroidal anti-inflammatory drugs. The naturopathic agents also being studied include polyphenolics, antioxidants, flavonoids, coenzyme Q, and thiamine. Cell systems studied include isolated hepatocytes and tumor cell cultures.
"Accelerated Cytotoxic Mechanism Screening (ACMS)". Techniques have been developed to supplement the high throughput in vitro techniques currently in use for screening and prioritising new drug candidates. These are used to evaluate drug safety and drug interactions before selecting the lead candidates for animal toxicity testing and clinical trials. Quantitative Structure Activity Relationships based on physiochemical properties are also being developed for computer-based toxicity predictive models for early ADMET screening so as to decrease drug discovery and development times. An example of a common drug candidate cytotoxic mechanism found using ACMS screening toxicity was mitochondrial toxicity that caused reductive stress and ATP depletion, released iron and activated oxygen. This cytotoxic mechanism could be prevented by antioxidants, iron chelation or by restoring cellular redox potential. Apoptosis inhibitors e.g. inhibitors of the mitochondrial permeability transition, caspases, protein synthesis or RNA transcription also prevented this cytotoxic mechanism.
The above should provide a useful working hypothesis to understand various disease states as well as help design safer drugs and better methods for treating diseases.
Lee O,Bruce WR, Dong Q, Bruce J, Mehta R and O’Brien PJ. Fructose and carbonyl metabolites as endogenous toxins. Chemico-Biol.Interacn. 2009; 178, 332-9.
Banach MS , Dong Q and O’Brien PJ. Hepatocyte Cytotoxicity Induced by Hydroperoxide (Oxidative stress) or Glyoxal (Protein Carbonylation Model): Prevention by Bioactive Nut Extracts or Catechins. Chemico-Biol.Interacn. 2009; 178, 324-31.
Tafazoli S and O’Brien PJ. Amodiaquine-induced oxidative stress in a hepatocyte inflammation model. Toxicology. 2009; 256,101-9.
Martin JW,Chan K,Mabury SA, O’Brien PJ. Bioactivation of Fluorotelomer Alcohol in Isolated Rat Hepatocytes. Chemico-Biol.Interacn. 2009; 177,196-203.
Tafazoli S and O’Brien PJ. Accelerated cytotoxic mechanism screening of hydralazine using an in vitro hepatocyte inflammation model Chem.Res.Toxicol. 2008; 21,904-910.
Tafazoli S , Mashregi M and O’Brien PJ. Role of Hydrazine in Isoniazid-Induced Hepatotoxicity in a Hepatocyte Inflammation Model. Toxicol. Appl. Pharmacol. 2008; 229,94-101.
Leslie Dan Faculty of Pharmacy
University of Toronto
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