TISSUE-SPECIFIC INDUCTION OF MUTATIONS BY STREPTOZOTOCIN IN-VIVO

Streptozotocin has been reported to induce DNA damage in mouse liver although malignant tumors were not induced in this organ. DNA damage had not yet been monitored in the mouse kidney which was the tumor target organ in two mouse studies. In order to elucidate target organ specificity of genotoxicity and of tumorigenesis, we investigated the induction of DNA damage (microgel electrophoresis assay) and mutations (Lad transgenic mouse mutation assay) in the fiver and kidney of male C57BL/6 mice. Our results show that the microgel electrophoresis assay was more sensitive and revealed the genotoxic potential of streptozotocin at lower doses than the mutation assay. It was, however, less specific in that DNA damage was induced both in target and non-target tissues of carcinogenesis at a similar potency. In contrast, the mutation analysis revealed the kidney to be more sensitive when the induced mutation frequencies are expressed as a multiple of the respective spontaneous rates. We conclude, therefore, that the carcinogenic organotropy of streptozotocin correlates better with its tissue-specific mutagenicity than with its pattern of inducing DNA damage when the two in vivo genotoxicity assays mentioned above are used. A combined use of the microgel electrophoresis assay and the transgenic mouse mutation assay is proposed for investigations of tissue-specific genotoxicity.