Reduction of Copper(II)-Bleomycin: A Model for in Vivo Drug Activity

The effect of aliphatic thiols, including glutathione, cysteine, and dithiothreitol, on the anaerobic reduction of Cu(II)-bleomycin was examined. At neutral pH, cysteine is more efficient in reducing Cu(II)-bleomycin than either dithiothreitol or glutathione, while at alkaline pH the rate of reduction with all three reagents increases substantially. A kinetic treatment suggests that 2 equiv of thiol is required for each mole of Cu(II)-bleomycin reduced. Material balance studies verify this stoichiometry. If anaerobic reduction of Cu(II)-bleomycin is carried out in the presence of Fe(II), iron is chelated by the drug. This metal-drug complex is capable of degrading DNA when O₂ is introduced. The extent of DNA degradation, as measured by the release of malondialdehyde-like chromogens from the DNA, is directly dependent on the amount of Cu(II)-bleomycin reduced.