Our molecular toxicology program focuses on the molecular events involved in drug and chemical toxicity. The toxicity of many xenobiotics is dependent on the formation of reactive intermediates (RI). RI are usually formed through metabolic transformation and may lead to organ damage, cancer, or birth defects through interaction with proteins, lipids, and/or DNA. RI may damage cellular constituents directly or through the generation of additional reactive species, such as superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. Expression of toxicity is ultimately dependent on the balance between the formation and elimination of the RI, the balance between the cellular damage and the cellular repair or defense systems, and the response of the cell or body to the damage caused by the RI. The long term goal of our research program is to understand how molecular events are linked to and modify drug and chemical-induced toxicities and to use this information to understand individual human and species differences in response to drugs. We are particularly interested in the molecular events involved in idiosyncratic drug reactions, as we are currently unable to predict this events clinically or during the drug development process. While our pharmacogenetics program emphasizes the metabolic aspects of this research, our molecular toxicology program focuses on the links between covalent binding, the immune response thought to play an important role in idiosyncratic toxicity, and clinical toxicity. We are interested in the role of specific target proteins as well as in novel cell defence pathways. Therefore, a considerable portion of our efforts are currently devoted to endoplasmic reticulum stress/chaperone proteins and their role in determining cytotoxic events. Results from our laboratory have shown that the effects of these proteins are cell and toxin specific.

Examples of recent publications from our molecular toxicology program:

Cribb AE, Nuss CE, Alberts DW, Lamphere DB, Grant DM, Grossman SJ, and Spielberg SP. Covalent binding of sulfamethoxazole reactive metabolites to human and rat liver subcellular fractions assessed by immunochemical detection. Chem. Res. Toxicol., 9; 500-507, 1996

Cribb AE, Belle L, Trepanier L, Spielberg SP. Adverse reactions to sulphonamide and sulphonamide-trimethoprim combination products: clinical syndromes and pathogenesis. Adverse Drug Reactions and Toxicological Reviews, 15: 9-50, 1996

Cribb AE, Pohl L, Spielberg SP, Leeder JS. Patients with delayed onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins. Journal of Pharmacology and Experimental Therapeutics, 282: 1064-72, 1997.

Gaskill C, Burton S, Gelens H, Ihle S, Miller J, Shaw D, Brimacombe M, Cribb A. Effects of phenobarbital on serum thyroxine and thyroid stimulating hormone in epileptic dogs. J Am Vet Med Assoc, 215: 489-496, 1999.

Bedard K, Smith S, Cribb A. Sequential assessment of an anti-drug antibody response in a patient with a systemic delayed-onset sulfonamide hypersensitivity reaction. Br J Dermatology, 142: 253-58, 2000

Gaskill C, Burton S, Gelens H, Ihle S, Miller J, Shaw D, Brimacombe M, Cribb A. Changes in serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs receiving phenobarbital for one year. J Vet Pharmacol Ther, 23: 243-49, 2000

Bedard K, Fuentealba C, Cribb A. The Long Evans Cinnamon (LEC) rat develops hepatocellular damage in the absence of antimicrosomal antimbodies. Toxicology, 146: 101-109, 2000.

Gaskill C, Cribb A. Hepatic changes associated with phenobarbital therapy in epileptic dogs. Society of Toxicology, Philadelphia, March, 2000

Bedard K, Cribb A. Differential protection against cytotoxins in HepG2 cells after endoplasmic reticulum stress. ISSX 2000, June, 2000.

Summan M, Cribb A. Sulfamethoxazole hydroxylamine covalent binding and cytotoxicity in U937 cells. Eurotox 2000, September, 2000.

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