There is substantial evidence that important environmental agents of concern for human health exert biological toxicity by redox- cycling to create oxidant stress in aerobic cells and tissues. Included are components of smog pollution (NO2, ozone); the herbicide paraquat; pharmacological substances such as alloxan and 6-hydroxy dopamine; the antibiotics nitrofurantoin and streptonigrin; the cancer chemotherapeutics bleomycin, adriamycin (doxorubicin) and mitomycin C; and oxygen itself. Increased industrial, agricultural and pharmacologic applications have increased the kinds and amounts of xenobiotic redox-active agents to which humans are exposed. The most generally accepted toxicity hypothesis is that these agents accept electrons singly and pass them on to oxygen through a succession of intermediates, leading ultimately to HO., perhaps by iron-catalyzed Fenton chemistry. Cellular antioxidant defenses may be overwhelmed, causing damage or death. Evidence also supports roles for oxygen radicals in tissue damage from ischemia-reperfusion (as in myocardial infarction) and in the aging process. We propose to continue basic toxicological investigations of the cellular sites and mechanisms by which damage occurs via oxidant stress. Our research has been and continues to be primarily designed to uncover specific cellular sites of toxicity. We now are able to focus on understanding why and how a few key enzymes in a bacterial model appear to be an order of magnitude more sensitive than the remaining machinery of the cell, and to use these identified sites for assessing the comparative importance of cellular defenses identified by other researchers. Thus, the research is aimed at fundamental evaluation of the oxidant stress/redox cycling mechanisms of action for toxic substances containing odd electrons (including oxygen itself) and ultimately for understanding the delicate balance provided by nature between the necessary biological use of oxygen and its toxic potential. The novel aspects of the proposed work are twofold: (a) specific cellular and enzyme damage sites can now be assessed in coordination with the current operant scheme of cellular defenses through the availability of bacterial mutants which are deficient in, or which overproduce superoxide dismutase and (b) the identified sensitive enzymes provide a unique opportunity to study the mechanism of enzyme inactivation and to develop a unifying theory with predictive value for identifying other oxidant- sensitive enzymes.
Showing the most recent 10 out of 15 publications
