Tumorigenicity of racemic and optically pure bay region diol epoxides and other derivatives of the nitrogen heterocycle dibenz[a,h]acridine on mouse skin

CD-1 female mice were initiated with a single topical application of 500 mm ol dibenz[a,h]acridine (DB[a,h]Acr), its racemic trans-1,2-, 3,4-, 8,9- and 10,11-dihydrodiols, racemic DB[a,h]Acr 3,4-diol 1,2-epoxide-1 and -2 or ra cemic DB[a,h]Acr 10,11-diol 8,9-epoxide-1 and -2, where the benzylic hydrox yl group is either cis (isomer 1) or trans (isomer 2) to the epoxide oxygen . The mice were subsequently treated twice weekly with 12-O-tetradecanoyl-p horbol 13-acetate for 25 weeks. High tumorigenicity was observed only for D B[a,h]Acr, its 10,11-dihydrodiol and DB[a,h]Acr 10,11-diol 8,9-epoxide-2 (3 .3, 1.2 and 1.6 tumors/mouse, respectively). The tumor-initiating activity of a 50 nmol dose of DB[a,h]Acr and the optically active (+)- and (-)-enant iomers of DB[a,h]Acr 10,11-dihydrodiol and of the optically active DB[a,h]A cr 10,11 diol 8,9-epoxide-1 and -2 were also studied. Only DB[a,h]Acr, (-)D B[a,h]Acr (10R,11R)-dihydrodiol and the bay region(+)-(8R,9S,10S,11R)-diol epoxide-2 were highly active (1.6, 1.7 and 2.4 tumors/mouse, respectively). These results are consistent with previous studies which showed that the c orresponding bay region RSSR diol epoxides of benzo[a]pyrene, benz[a]anthra cene, chrysene and benzo[c]phenanthrene as well as the aza-polycyclic diben z[c,h]acridine are the most tumorigenic isomers.