Covalent Binding of 7,12-Dimethylbenz(a)anthracene and 10-Fluoro-7,12- dimethylbenz(a)anthracene to Mouse Epidermal DMA and Its Relationship to Tumor-initiating Activity1

10-Fluoro-7,12-dimethylbenz(a)anthracene (10-F-DMBA) is a more potent skin tumor initiator in SENCAR mice when com pared with the parent hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA). To elucidate the mechanism for this difference, the covalent binding of these two hydrocarbons to the DMA of mouse epidermal cells in vivo and in vitro was compared. The quantity of 10-F-DMBA covalently bound to mouse epidermal DNA in vivo was greater than that of DMBA at all doses tested over the range of 4 to 200 nmol/mouse. The magnitude of this binding difference between 10-F-DMBA and DMBA was greater at the higher doses (e.g., 1.5-fold at 4 nmol/mouse versus 3.4fold at 200 nmol/mouse). These results correlated closely with the dose-response relationships for tumor initiation by the two hydrocarbons. Analysis of the isolated DNA samples by Servacel DHB chromatography revealed the relative proportion of syndiol-epoxide:DNA adducts derived from DMBA increased dra matically as a function of dose (~30% at 4 nmol/mouse versus ~55% at 200 nmol/mouse). Conversely, the relative proportion of syn-diol-epoxide adducts derived from 10-F-DMBA was low and remained essentially constant over the same dose range. High-pressure liquid Chromatographie analyses of the DNA adducts derived from DMBAand 10-F-DMBA-treated mice re vealed qualitatively similar profiles. However, as expected, there was a marked reduction in the relative proportion of syn-diolepoxide:DNA adducts in the profiles of epidermal samples from 10-F-DMBA-treated mice. The major syn-diol-epoxide:deoxyadenosine adduct was present at a level only 30% that found in high-pressure liquid Chromatographie profiles of DMBA samples. Similar results were obtained when primary cultures of mouse epidermal cells were treated with the hydrocarbons. The results suggest that the increased total binding and possibly the de creased proportion of syn-diol-epoxide: DNA adducts confer greater tumor-initiating potency on 10-F-DMBA.