Studies on the interaction of bleomycin A₂ with rat lung microsomes. I. Characterization of factors which influence bleomycin-mediated DNA chain breakage

The interaction of bleomycin A₂ with rat lung microsomes has been investigated to determine whether DNA chain breakage or microsomal lipid peroxidation occurred, as these reactions could contribute significantly to bleomycin-induced lung injury. In the presence of calf thymus DNA and NADPH or NADH, significant oxygen-dependent, bleomycin-mediated DNA chain breakage was observed. In the absence of DNA, however, bleomycin did not stimulate microsomal lipid peroxidation. Moreover, incubation of bleomycin with rat lung microsomes in the absence of DNA resulted in a time-dependent decline in the ability of bleomycin to subsequently mediate DNA damage. This microsome-catalyzed inactivation of bleomycin was found to be dependent of both oxygen and NADPH, suggesting that a similar mechanism may be involved in bleomycin-mediated DNA damage and bleomycin inactivation. In addition to microsomes from rat lung, microsomes from mouse and rabbit lung and from rat liver and kidney catalyzed bleomycin-mediated DNA damage. These observations suggest that although a bleomycin-microsome interaction and subsequent DNA damage could be involved in bleomycin-induced lung injury, this interaction alone cannot account for the organ-specific toxicity of bleomycin toward the lung.