There is substantial evidence that important environmental agents of concern for human health exert biological toxicity by redox-cycling in aerobic cells and tissues. Included are components of smog pollution (NO2, ozone); the herbicide paraquat; therapeutic and pharmacological substances such as alloxan and 6-hydroxy dopamine; the antibiotics nitrofurantoin and streptonigrin; the cancer chemotherapeutics bleomycin, adriamycin and mitomycin C; and oxygen itself. These agents possess unpaired electrons, accept electrons singly and may pass them on to oxygen. A succession of intermediates leading ultimately to the hydroxyl radical, perhaps by Fenton chemistry, may occur. Cellular antioxidant defenses may be overwhelmed, causing damage or death. Industrial and agricultural uses and development of new therapeutic agents have increased the amounts and kinds of such redox-active substances to which humans are exposed. We propose basic biochemical and toxicological investigations of the cellular sites and mechanisms by which damage occurs via oxidant stress. We shall employ a selection of chemicals which share the ability to accept electrons singly, as models. We propose cellular, biochemically oriented research in vitro and in vivo using bacteria, rats and mice. The objectives are to evaluate the thesis that previously discovered damage sites from oxygen (which were extended in part to paraquat by the research which forms the basis of this renewal proposal), are valid for selected, other redox-active compounds; to evaluate potential circumvention of the consequences of such damage by providing intermediates or products such as specific amino acids, niacin and thiamine which are beyond the enzyme blocks in pathways which are poisoned; and to pinpoint the damage sites in thiamine metabolism and to more fully characterize the mechanisms involved in impairment of niacin-NAD biosynthesis, and for strigency induction. The research thus should lead to a basis for better evaluation of the oxidant stress/redox-cycling mechanism of action for toxic substances containing odd electrons; to identification of specific damage sites and mechanisms for specific agents; and ultimately to mitigating the toxicity of these agents while extending their commercial benefits and environmental safety.
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