Activation of nitrosamines and other carcinogens by mouse-liver S9, mouse hepatocytes and in the host-mediated assay produces different mutagenic responses in Salmonella TA1535.
5 indirect alkylating carcinogens, namely, dimethylnitrosamine (DMNA), methylethylnitrosamine (MENA), diethylnitrosamine (DENA), 1,2-dimethylhydrazine (DMH) and cyclophosphamide (CP), were tested in liquid incubation assays for their mutagenic activity towards Salmonella TA1535 in the presence of mouse-liver homogenate (S9) or freshly isolated, single liver-cell preparations. The capacity of these mouse-liver preparations to activate the compounds to mutagens for TA1535 was compared with the mutagenic effect of low doses of the carcinogens in intrasanguineous host-mediated assays, with the same strain of mice as host. Although the mouse hepatocytes retained their activating capacity longer than S9 preparations did during incubation at 37 degrees C, the latter gave much higher yields of mutants with 10 mM (DMNA, MENA, DMH) and 5 mM (CP) of 4 out of the 5 compounds. DENA was not mutagenic in either assay. These differences between whole cell and disrupted cell preparations were reduced or absent when the concentrations of the test compounds were reduced by a factor of 10. It was concluded that hepatocytes at the maximal concentration of cells have a limited capacity to metabolize the mutagens. On the basis of protein concentration, hepatocytes are more effective (nitrosamines) or equally effective (CP and DMH) in activating the compounds. Compared with the host-mediated assays, both liver fractions have only a marginal potential to activate equal low amounts of the carcinogens. The present results do not indicate that hepatocytes take an 'intermediate' position between existing in vitro and in vivo activation systems, although they do suggest that these mouse hepatocyte preparations activate the nitrosamines DMNA and MENA in a quantitatively or qualitatively different way than do mouse-liver homogenates.
D019813:1,2-Dimethylhydrazine; D000818:Animals; D001711:Biotransformation; D003520:Cyclophosphamide / Q000378:metabolism; D004052:Diethylnitrosamine / Q000378:metabolism; D004127:Dimethylhydrazines / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009152:Mutagenicity Tests; D009602:Nitrosamines / Q000378:metabolism*; D012475:Salmonella / Q000187:drug effects; D013997:Time Factors
D004127:Dimethylhydrazines; D009602:Nitrosamines; D004052:Diethylnitrosamine; D003520:Cyclophosphamide; D019813:1,2-Dimethylhydrazine; D004128:Dimethylnitrosamine