Interdependent toxicity mechanisms of oxidative stress, thiamin deficiency and alpha-oxoaldehydes

Oxidative stress and thiamin deficiency are prevalent in diseases such as diabetes mellitus. An increase in oxidative stress and thiamin deficiency leads to an increase in alpha-oxoaldehydes (i.e. reactive dicarbonyls, glyoxal and methylglyoxal (MG)) which are known to be cytotoxic. This thesis investigated the relationship between alpha-oxoaldehyde induced oxidative stress, thiamin deficiency and toxicity. Chapter 2 describes the molecular mechanisms of rat hepatocyte cytotoxicity induced by the alpha-oxoaldehyde, glyoxal. An increase in reactive oxygen species (ROS), lipid peroxidation, glutathione (GSH) depletion and a decrease in mitochondrial membrane potential were observed before glyoxal-induced cell death occurred. Glyoxal-induced oxidative stress and cytotoxicity were prevented by aminoguanidine, D-penicillamine and pyridoxamine. Chapter 3 describes the role of thiamin in glyoxal detoxification by maintaining cellular NADPH levels. Under thiamin deficient conditions, glyoxal cytotoxicity and oxidative stress were increased. These were prevented by supplementing the media with 3 mM thiamin or 5 mM benfotiamine (lipophilic derivative of thiamin). In Chapters 4 and 5, rats exposed to exogenous oxidative stress and dietary thiamin deficiency resulted in increased levels of plasma glyoxal/MG and their hydroimidazolone protein adducts. In chapter 5, rats given a heat treated diet (thermolyzed diet) that was low in thiamin resulted in decreased GSH and increased levels of liver and colon oxidative stress biomarkers such as nitrotyrosine, protein carbonyls and hydroimidazolones. There was also an increased infiltration of macrophages in the colon indicating that inflammation had occurred. Increased alpha-oxoaldehyde levels led to an increased body burden of advanced glycation end products (AGES) which decreased GSH dependent antioxidant defenses. Thiamin deficiency and oxidative stress produced high levels of endogenous glyoxal/MG that could increase the risk of pre-neoplastic or neoplastic conditions in the colon.