The research described herein is an initial effort to assess the importance of a particular metabolic process, the reductive cleavage of a carbon-oxygen bond, to the biological activity of anthracycline antibiotics and arene oxide mutagens. The hypotheses to be tested for these compounds are the folhowing: Is there a direct relationship between the reductive cleavage of the anthracyclinone-glycoside bond and the toxicity of anthracyclines? What is the chemical mechanism of this process and how may this information be of value to the overall understanding of these compounds' biological activity? Does the ability of arene oxides to act as potent chemical oxidants (during which the epoxide is opened) provide a new correlation from which to predict their biological activity? The experimental approach to be used is identical for the two systems. Firstly, the chemical mechanism of these reductive processes with simple reducing agents (such as dihydronicotinamides and dihydroflavins) will be determined. Then, using anthracyclines and arene oxides of different structure, a connection between the rates and yields of their reduction and their individual structure will be sought. With this information in hand, the enzymes of the erythrocyte that effect the reduction of methemoglobin to hemoglobin will be examined as adventitious catalysts of these reactions. This will provide a basis for the subsequent investigation of the relationship that may exist between reductive metabolism of xenobiotics and the deleterious consequences of such metabolism (particuarly membrane degeneration), using the intact erythrocyte as a model.
NIH ExPorter
NIH ExPorter