Chemical and Molecular Biological Aspects of Alkylhydrazine-Induced Carcinogenesis in Human Cells in Vitro

摘要

Metabolic activation of methylhydrazines (MMH, DMH) was studied in cultured human fibroblast cell medium. Binding of DMH and MMH to both cell DNA and protein was observed and quantitated by using radioactive 14C-methylhydrazines. The cellular binding study will help us to understand the differences in toxicity or carcinogenicity of the various alkyl hydrazines. Synthesis of 14C-MMH was completed and 14C-UDMH will by synthesized during the second year. Alkylated DNA was hydrolyzed by using hydrochloric acid to the bases and the latter were separated by using HPLC. For MMH and DMH which were non-transformers of human cells, most of the binding was found to be at the phosphodiester oxygens. The binding to the bases was either low (DMH) or absent (MMH). It is hypothesized that the alkylation of phosphodiesters might contribute to the toxicity of these chemicals whereas the alkylation of bases, especially at the 0-6 position of guanine, might contribute to their carcinogenicity. Further investigations with 14C-UDMH will, hopefully, substantiate this hypothesis and studies are in progress towards this goal. (Author)