The effect of steric strain in the bay-region of polycyclic aromatic hydrocarbons: tumorigenicity of alkyl-substituted benz[a]anthracenes.
3,6-Dimethylcholanthrene (3,6-DMC) and 7,11,12-trimethylbenz[a]anthrene (7,11,12-TMBA) were tested for tumor-initiating activity on mouse skin as an approach to evaluate the potential role of steric strain in the bay-region on tumorigenic potency. Methyl-substitution at the 6-position of 3-methylcholanthrene (3-MC) increases steric strain in the bay-region of the hydrocarbon as it does at the 12-position of benz[a]anthracene (BA) causing both hydrocarbons to become non-planar. 3,6-DMC had at least 2- to 3-fold higher tumor-initiating activity than did 3-MC. Introduction of an 11-methyl group in 7,12-dimethylbenz[a]anthracene (7,12-DMBA) results in the formation of a more highly hindered (buttressing effect) hydrocarbon. 7,11,12-TMBA had 5% or less of the tumor-initiating activity of 7,12-DMBA, although the hydrocarbon still had relatively high tumorigenic activity on mouse skin. The results obtained with 3,6-DMC and studies reported previously with other methyl-substituted hydrocarbons, show that hydrocarbons possessing steric strain in the bay-region of the molecule can have enhanced tumorigenic activity. The basis of this steric effect remains unclear, however, as a result of the decreased tumorigenic activity of the 11-methyl-substituted derivative of 7,12-DMBA. The weak tumor-initiating activity of BA was enhanced at least 4- to 8-fold as a result of methyl-substitution at the 6- and 8-positions (6,8-dimethylbenz[a]anthracene). The higher tumorigenic activity of 6,8-dimethylbenz[a]anthracene compared to BA is consistent with a presumed decrease in metabolic detoxification of the dimethyl-substituted derivative at the 5,6- and 8,9-double bonds.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives / Q000633:toxicity*; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D002273:Carcinogens; D005260:Female; D008748:Methylcholanthrene / Q000031:analogs & derivatives* / Q000633:toxicity; D051379:Mice; D012878:Skin Neoplasms / Q000139:chemically induced*; D013329:Structure-Activity Relationship
D001551:Benz(a)Anthracenes; D002273:Carcinogens; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene; C040385:7,11,12-trimethylbenz(a)anthracene; C040386:3,6-dimethylcholanthrene