Activation-dependent carcinogens, mutagenicity

In the heptatocyte-mediated mutagenesis studies, freshly isolated hepatocytes were mixed in a ratio of about 2 1 with liver epithelial cells before inoculation into culture flasks. After attachment, the two cell types were found to be well mixed and in close contact. Exposure of mixed cultures to several activation-dependent carcinogens that produce DNA repair in hepatocytes also produced mutagenesis in the cocultivated rat liver epithelial lines (Table 7) under conditions of exposure in which the carcinogens were not mutagenic to the lines in the absence of cocultivated hepatocytes. Thus, activated metabolites produced by the hepatocytes were transferred to the epithelial cells. Efforts to simplify this assay by the use of stored frozen hepatocytes are in progress. 

The QSARs show that for both bacterial mutagenicity and rodent carcinogenicity, the gradation of the potency of the active aromatic amines first depends on hydrophobicity, and then depends on electronic and steric properties. This confirms the existence of a common first step in the mutagenicity and carcinogenicity of these compounds, and adds confidence to the models obtained. 

Studies on the consequences of stereoselective PAH metabolism in respect to mutagenicity and carcinogenicity were also shown to be strongly dependent on the relative and absolute configuration of the PAH metabolite (Conney, 1982 Thakker et al., 1982). For example, (-)-7R,8R-dihydrodiol benzo[a]pyrene has a 10-foId higher tumor-initiating activity in female CD-I mouse skin than the (+)-7S,8S-enantiomer, and it produces... 

---