The role of electron transfer reactions in the cytotoxicity mechanism of xenobiotics

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Foreign chemical are found in the environment as industrial byproducts, pollution, and may be encountered through occupational exposure. Arylamines are a significant group of foreign chemical that can interact with biological systems, like the cells of organs and tissues; this usually results in their transformation. Another word for this is metabolism, which, understandably, produces metabolites. These metabolites usually have properties that enable them to be removed from the cell. However, in certain instances, the metabolites can be harmful and react with the cells in such a way that results in their damage. These harmful metabolites are referred to as reactive metabolites as they usually tend to react with vital molecules of cells, such as proteins or DNA. **This proposal aims to study a specific type of reactive metabolite known as free radical metabolites. Arylamines can interact with specific proteins (enzymes) that can metabolize the arylamines into arylamine free radical metabolites. The enzyme that this proposal deals with is called myeloperoxidase, which is found in leukemia cells, and white blood cells, and also bears resemblance to similar enzymes found in plants, animals, and microbes. Under specific conditions, when an arylamine comes into contact with myeloperoxidase, it can trigger metabolism that will produce reactive arylamine free radical metabolites. These metabolites are harmful to the cells if they react with vital molecules (discussed above). Usually, cells have mechanisms to remove these types of harmful metabolites through antioxidants, such as Vitamin C, Vitamin E, or glutathione. Reactions between arylamine free radical metabolites and antioxidants are an effective way of minimizing the damage that the former can cause. However, this proposal seeks to study other small molecules that the arylamine free radical metabolites can interact with which can lead to modulating the damage that they cause. These are termed electron transfer intermediates (ETIs) because they are able to give their electrons to the arylamine free radical metabolite so that it is no longer damaging. Preliminary findings have shown that certain ETIs have characteristics that enable them to effectively scavenge arylamine free radical metabolites, but at the same time results in the production of new free radical metabolites formed on the ETI. It is currently unknown how much more toxic are the ETI free radicals compared to the arylamine free radical metabolites which produced them, nor is it known if the ETI free radicals can cause more or less damage to the vital molecules (discussed above). Importantly, certain ETIs are found inside cells, so if their levels fluctuate there could be a variation in their reactions with arylamine free radical metabolites.**The objective of this study is to understand the consequences, at the cellular level, of which free radicals are more harmful to vital molecules and the cell as a whole. Specific objectives will focus on: 1) characterization what happens when the arylamine free radical metabolites and ETI interact by using techniques that can characterize free radicals, measure the interaction between arylamine free radical metabolites and ETIs, and develop equations to identify the chemical characteristics that predict these interactions; 2) compare protein and DNA damage caused by arylamine free radical metabolites in the presence/absence of ETIs, and 3) understanding the mechanism of cell death that is occurring when these reactions are taking place. **Trainees that are involved in these specialized studies will become experts in free radicals in living systems, which will be relevant for Canadian industry, academia, or government.