High stereoselectivity among the optical isomers of the diastereomeric bay-region diol-epoxides of benz(a)anthracene in the expression of tumorigenic activity in murine tumor models.
The tumorigenicity of the (+)- and (-)-enantiomers of the diastereomeric bay-region benz(a)anthracene 3,4-diol-1,2-epoxides was evaluated in two mouse tumor models. In an initiation-promotion experiment on mouse skin, a single topical application of 0.1 or 0.4 mumol of the benz(a)anthracene diol-epoxides was followed by 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Of the four isomers of the bay-region diol-epoxides, only (+)-[1R,2S,3S,4R]-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenz(a)anthracene [(+)-diol-epoxide-2] and (+)-[1R,2S,3S,4S]-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenz(a)anthracene [(+)-diol-epoxide-1] had significant tumor-initiating activity. (+)-Diol-epoxide-2 was approximately 4-fold more active as a tumor initiator on mouse skin than was (+)-diolepoxide-1 at both doses tested. In newborn mice, a total of 0.14 mumol of compound, divided into three doses, was administered i.p. on the first, eighth, and fifteenth day of life, and tumorigenic activity was determined when the mice were 26 to 32 weeks of age. As was observed in the initiation-promotion experiment on mouse skin, only two of the four optical isomers of the bay-region diol-epoxides produced a significant tumor incidence. (+)-Diol-epoxide-2 induced a 100% incidence of lung tumors, with an average of 23.11 tumors/mouse, and was at least 60-fold more active (average number of tumors per mouse) than was (+)-diol-epoxide-1, which produced a 31% lung tumor incidence and 0.38 lung tumors/mouse. (+)-Diol-epoxide-2 was the only optical isomer that induced a significant incidence of hepatic tumors in male mice (31% incidence, 1.17 tumors/mouse). The highly tumorigenic (+)-diol-epoxide-2 isomer with [R,S,S,R] absolute configuration has the same absolute configuration as does the highly tumorigenic isomer of the bay-region diol-epoxides of benzo(a)pyrene and chrysene.
D000818:Animals; D000831:Animals, Newborn; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002273:Carcinogens; D005260:Female; D007536:Isomerism; D008113:Liver Neoplasms / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D012737:Sex Factors; D012878:Skin Neoplasms / Q000139:chemically induced*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001551:Benz(a)Anthracenes; D002273:Carcinogens; C015149:benzanthracene-3,4-dihydrodiol