Effect of Misonidazole Pretreatment on Nitrogen Mustard-induced DNA Cross-linking in Mouse Tissues in Vivo

In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g-1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver (X 6) and kidney (X 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.