Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity.

The biochemical basis for bleomycin-induced pulmonary toxicity was studied in vitro and in vivo with an improved HPLC system. The in vitro metabolism of bleomycin A2 to desamido-bleomycin A2 was measured in tissue homogenates from a species sensitive (mice) and relatively resistant (rabbits) to the pulmonary fibrogenic properties of bleomycin. Lung tissue from mice lacked detectable bleomycin hydrolase activity, whereas rabbit lung tissue homogenates had high levels of the enzyme activity, equaling that seen in rabbit kidneys and spleen. Injection of radiolabeled bleomycin A2 into mice demonstrated that only a small percentage of the total dose was taken up by any organ and that extensive metabolism of this drug occurred within 1 hr in liver, kidneys, and spleen but not in lungs in vivo. In addition, metabolites other than desamido-bleomycin A2 were prominent, and their relative amounts increased with time. Mice injected subcutaneously with bleomycin A2 developed pulmonary fibrosis, while animals treated with equivalent doses of desamido-bleomycin A2 did not, indicating that this metabolite is not as toxic to the lungs as is the parent compound. These results provide direct evidence that metabolism plays a major role in determining the toxic potential of bleomycin to the lungs.