Bleomycin toxicity. Alterations in oxidative metabolism in lung and liver microsomal fractions

Abstract

Separate groups of male rats received low doses (5 units) or high doses (15 units) of bleomycin i.p. twice weekly for 1.5, 3 or 6 weeks. The susceptibility of tissue lipid to peroxidation and the activities of mixed function oxidations were examined in microsomal fractions prepared from lung and liver. ADP-Fe (III)-initiated lipid peroxidation was stimulated in lung microsomal fractions only in animals treated with high-dose bleomycin for 1.5 weeks, whereas a 2- to 4-fold enhancement was observed in liver preparations from all bleomycin-treated animals. Microsomal ADP-Fe (III)-initiated lipid peroxidation was inhibited, however, by the in vitro addition of bleomycin in both lung and liver preparations, but this inhibition was an artifact resulting from the chelation of Fe (III) by bleomycin. Soybean lipoxygenase I-initiated microsomal lipid peroxidation, which does not require added iron, was unaffected by bleomycin in lung preparations but was inhibited in liver. Following in vivo treatment, lung microsomal hydrogen peroxide generation was inhibited by 1.5 weeks of high-dose bleomycin treatments, whereas benzphetamine N-demethylation was unchanged. These cytochrome P-450-dependent reactions were both suppressed, however, in liver microsomal fractions. In vitro, both reactions were also inhibited by bleomycin in liver but not in lung microsomal fractions. The lack of effect of in vitro bleomycin treatments on superoxide generation in lung or liver preparations suggests that the NADPH cytochrome P-450 reductase component of the mixed function oxidase system was not affected. Minimal alterations in lipid peroxidizability and mixed function oxidase activities in lung microsomal fractions of bleomycin-treated animals suggest that the insensitivity could be due to: (1) the site of toxicity not being at the level of the endoplasmic reticulum; or (2) the target of bleomycin toxicity being limited to a small population of pulmonary cell types. Even though the liver is not susceptible to bleomycin toxicity, the hepatic microsomal mixed function oxidase system is highly sensitive to this chemical.