Mutagenicity and cytotoxicity of benz[alpha]anthracene diol epoxides and tetrahydro-epoxides: exceptional activity of the bay region 1,2-epoxides.
Three diastereomeric pairs of diol epoxides, two tetrahydro-epoxides, and the K-region oxide of the polycyclic aromatic hydrocarbon benz[a]anthracene were evaluated for mutagenic activity in strain TA 100 of Salmonella typhimurium and in line V79-6 of Chinese hamster lung cells. The two diastereomeric 1,2-epoxides of the trans-3,4-dihydrodiol of benz[a]anthracene are 15 to 35 times more mutagenic to the bacteria and 65 to 125 times more mutagenic to the mammalian cells than are the diastereomeric pairs of benz[a]anthracene-8,9-diol-10,11-epoxides or benz[a]anthracene-10,11-diol-8,9-epoxides. 1,2-Epoxy-1,2,3,4-tetrahydrobenz[a]anthracene is the most mutagenic and cytotoxic of the nine derivatives and is 5 and 25 times more mutagenic than 3,4-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene in bacterial and mammalian cells, respectively. In either test system, benz[a]anthracene 5,6-oxide (K-region oxide) has less than 10% of the activity of any of the 1,2-epoxides derived from benz[a]anthracene. The relative stabilities of the derivatives in aqueous solution do not account for the differences in mutagenic activity because the more mutagenic derivatives tend to be less stable. The benz[a]anthracene diol epoxides, like the benzo[a]pyrene diol epoxides, are refractory to the action of epoxide hydrase. The exceptional mutagenic activity of the 1,2-epoxide derivatives of benz[a]anthracene is consistent with and supportive of the hypothesis that bay region epoxides on saturated, angular benzo-rings of unsubstituted polycyclic aromatic hydrocarbons are ultimate carcinogens.
D001551:Benz(a)Anthracenes / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000378:metabolism; D004988:Ethers, Cyclic; D008968:Molecular Conformation; D009153:Mutagens / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D001551:Benz(a)Anthracenes; D004988:Ethers, Cyclic; D009153:Mutagens; D004851:Epoxide Hydrolases