Chemical and Molecular Biological Aspects of Alkylhydrazine-Induced Carcinogenesis in Human Cells in vitro
Interim rept. 1 Sep 80-31 Aug 81
OHIO STATE UNIV RESEARCH FOUNDATION COLUMBUS
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14C-labeled 1,1-DMH and 1,2-DMH of high specific activity or 100 mCim mol have been prepared and utilized, along with 14C-labeled MMH, to study alkylation of DNA and proteins in low passage human neonatal foreskin derived fibroblasts. When human fibroblasts were treated under conditions which would be expected to lead to a negligible number of transformation events, i.e. cells labeled were in a non-growing environment and the dose of methylhydrazine 1.6 microgramml was well below the ED50 value 62-100 microgramml, significant differences in DNA and protein methylation were observed. For both protein and DNA, 1,2-DMH produced a higher degree of methylation than 1,1-DMH, with MMH demonstrating the lowest level. The relative quantity of 14CO2 released into the atmosphere above the treated fibroblast monolayers increased in order MMH 1, 1-DMH 1,2-DMH. The data suggests that in these cells there are significant differences in the metabolic andor chemical transformation of the methylhydrazines in the proposed active metabolite, methyl diazonium ion. The majority of label in DNA isolated from cells treated with 1,2- and 1,1-DMH was found in the apurinic acid fraction. This was in contrast to that observed for MMH, when the majority of label was found in unmodified adenine Ade and guanine Gua. Thus, in this latter case the carbon label appears to be more efficiently trapped in the 1-carbon pool than for the other methylhydrazines.
- Medicine and Medical Research