Mitomycin antibiotic reductive potential and related pharmacological activities.
Relationships of reductive potential, kinetics of enzymatic reduction, augmented oxygen consumption, and cytotoxicity were determined for seven clinically relevant mitomycin antibiotics. Potentials for one-electron reduction were obtained by cyclic voltammetry analysis in dimethyl sulfoxide with 0.1 M tetraethyl-ammonium perchlorate. These potentials were -0.55 V for N7-acetylmitomycin C, -0.61 V for mitomycin A, -0.75 V for N7-(p-hydroxyphenyl)mitomycin C, -0.79 V for N7-(dimethylamino-methylene)mitomycin C, -0.81 V for N7-(2-(4-nitrophenyldithio)-ethyl)-mitomycin C, -0.81 V for mitomycin C, and -0.89 V for porfiromycin. All seven antibiotics were reduced by xanthine oxidase and NADPH-cytochrome P450 reductase, but the rate of reduction varied for each antibiotic and each enzyme. The less negative the reductive potential of an antibiotic, the more easily that antibiotic was reduced enzymatically. These seven mitomycin antibiotics also augmented oxygen consumption by rat liver microsomes. As with their reduction by xanthine oxidase and NADPH-cytochrome P450 reductase, the less negative the reductive potential of an antibiotic, the more it augmented oxygen consumption. Cytotoxicity of each antibiotic was assessed by defining the IC50 against HCT 116 human colon carcinoma cells. A relationship between the reductive potential of these antibiotics and their cytotoxicity against HCT 116 cells was also observed.
Pan
S S
SS
Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore 21201.
Gonzalez
H
H
D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy; D004563:Electrochemistry; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology*; D009245:NADH Dehydrogenase / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000378:metabolism
D008937:Mitomycins; D016685:Mitomycin; D014969:Xanthine Oxidase; D009245:NADH Dehydrogenase