The effects of 21-aminosteroids on the redox status of iron in solution.
The effects of two 21-aminosteroids (U-74500A and U-74006F) on the oxidation and reduction of iron were investigated. U-74500A completely prevented ADP: Fe(II) autoxidation whereas U-74006F had only a slight inhibitory effect. The inhibition of Fe(II) oxidation by U-74500A was concentration dependent, with 100% inhibition occurring at concentrations equal to or greater than 25 microM in systems containing 50 microM Fe(II). When the Fe(II)-specific chelator Ferrozine was added to incubations containing U-74500A and ADP:Fe(II), formation of the Ferrozine:Fe(II) chromophore was slow, suggesting that U-74500A chelates Fe(II) with substantial affinity. Temporally, 20 min were required for complete formation of the Ferrozine-Fe(II) chromophore in the presence of U-74500A, whereas complexation in its absence was instantaneous. This phenomenon was not observed with U-74006F, Desferal, or ascorbate. In a system containing 25 microM ADP:Fe(II), U-74500A (25 microM) and U-74006F (25 microM) acted as iron reductants, reducing the iron at rates of approximately 2, and 0.1 microM/min, respectively. In addition, U-74500A fluorescence was quenched in a concentration-dependent manner upon the addition of Fe(III), further demonstrating interactions between this compound and iron. The substructures of U-74500A consist of a steroid (U-76911) and a complex amine (U-82902E). When these compounds were assayed individually, it was found that U-82902E exhibited activities similar to those of U-74500A, whereas the free steroid had no effect. Studies employing cyclic voltammetry revealed that U-74500A had a relatively low oxidation potential (E = 228 mV), whereas U-74006F was much less susceptible to oxidation (E = 810 mV). Taken together, these data suggest that subtle effects on iron redox chemistry, which would in turn inhibit or eliminate the initiation of undesired oxidative reactions, may contribute to the potent antioxidant activities of U-74500A and U-74006F.
Ryan
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Investigative Toxicology, Upjohn Laboratories, Kalamazoo, Michigan 49001.
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D000244:Adenosine Diphosphate; D000975:Antioxidants; D001205:Ascorbic Acid; D005297:Ferrozine; D007501:Iron / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011281:Pregnatrienes; D012996:Solutions; D013329:Structure-Activity Relationship; D013997:Time Factors
D000975:Antioxidants; D011281:Pregnatrienes; D012996:Solutions; D005297:Ferrozine; D000244:Adenosine Diphosphate; D007501:Iron; C053356:U 74500A; D001205:Ascorbic Acid; C053355:tirilazad