Both (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxides initiate tumors in mouse skin that possess -CAA- to -CTA- mutatiomsat codon 61 of c-H-ras

We have determined the tumor-initiating activity of (+/-)syn- and (+/-)anti -7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (syn- and anti-DMBADE) , the two metabolically formed bay-region diol epoxides of DMBA, and we hav e also analyzed mutations in the H-ras gene from tumors induced by these co mpounds. Using a two-stage, initiation-promotion protocol for tumorigenesis in mouse skin, we have found that both syn- and anti-DMBADE are active tum or initiators, and that the occurrence of papillomas is carcinogen dose dep endent. All of the papillomas induced by syn-DMBADE (a total of 40 mice), 9 6% of those induced by anti-DMBADE (a total of 25 mice), and 94% of those i nduced by DMBA (a total of 16 mice) possessed a -CAA- to -CTA- mutation at codon 61 of H-ras. No mutations in codons 12 or 13 were detected in any tum or. Topical application of syn- and anti-DMBADE produced stable adducts in mouse epidermal DNA, most of which comigrated with stable DNA adducts forme d after topical application of DMBA, Further analysis of the data showed th at levels of the major syn- and anti-DMBADE-deoxyadenosine adducts formed a fter topical application of DMBA are sufficient to account for the tumor-in itiating activity of this carcinogen on mouse skin. Previously, we showed t hat both the syn- and anti-DMBADE bind to the adenine (A(182)) at codon 61 of H-rns, Collectively, these results indicate that the adenine adducts ind uced by both bay-region diol epoxides of DMBA lead to the mutation at codon 61 of H-ras and, consequently, initiate tumorigenesis in mouse skin.