Mutagenicity of cyclopenta-fused isomers of benz(a)anthracene in bacterial and rodent cells and identification of the major rat liver microsomal metabolites.
The microsomal metabolites and mutagenic activity of four cyclopenta-fused benz(a)anthracenes, benz(j)aceanthrylene [B(j)A], benz(e)aceanthrylene [B(e)A], benz(l)aceanthrylene [B(l)A], and benz(k)acephenanthrylene [B(k)A], have been studied. Aroclor 1254-induced rat liver microsomes metabolized B(j)A to B(j)A-1,2-dihydrodiol, B(j)A-9,10-dihydrodiol, B(j)A-11,12-dihydrodiol, and 10-hydroxy-B(j)A; B(e)A-1,2-dihydrodiol, B(e)A-3,4-dihydrodiol, and B(e)A-5,6-dihydrodiol; B(l)A to B(l)A-1,2-dihydrodiol, B(l)A-4,5-dihydrodiol, and B(l)A-7,8-dihydrodiol; and B(k)A to B(k)A-4,5-dihydrodiol and B(k)A-8,9-dihydrodiol. With each polycyclic aromatic hydrocarbon, metabolism occurred on the cyclopenta ring. All four isomers were active as gene mutagens in Salmonella typhimurium and in Chinese hamster V79 cells. In the S. typhimurium mutation studies, using Aroclor 1254-induced rat liver S9, B(j)A, B(e)A, and B(l)A required significantly less microsomal protein for maximal mutation response than B(k)A and B(a)P, suggesting a one-step activation mechanism, presumably on the cyclopenta-fused ring. B(j)A, B(e)A, and B(l)A were significantly more mutagenic than B(k)A and B(a)P in S. typhimurium. In the Aroclor 1254-induced rat liver S9-mediated V79 mutagenesis system, all four isomers were active, with B(l)A the most active. When Syrian hamster embryo cells were used as the metabolic activation component for V79 cells, only B(l)A produced a significant response and was equivalent in activity to B(a)P. A helical configuration for B(l)A is inferred from the identification of two trans-B(l)A-1,2-dihydrodiols, syn and anti, which have been synthesized, separated, and characterized. The metabolically formed dihydrodiol is anti-trans-B(l)A-1,2-dihydrodiol, and experimental evidence suggests that the metabolically formed B(l)A-1,2-oxide is the anti-isomer. Synthetic B(l)A-1,2-oxide was found to be a direct-acting mutagen in S. typhimurium and Chinese hamster V79 cells and is estimated to account for up to 40% of the mutagenic activity of the parent hydrocarbon. Therefore, certain cyclopenta-ring fusions on benz(a)anthracene appear to markedly increase its genotoxic and carcinogenic activities.
D000818:Animals; D001551:Benz(a)Anthracenes / Q000138:chemical synthesis / Q000633:toxicity*; D001711:Biotransformation; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004351:Drug Resistance; D007536:Isomerism; D008168:Lung; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008748:Methylcholanthrene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013866:Thioguanine / Q000633:toxicity
D001551:Benz(a)Anthracenes; D009153:Mutagens; C041194:benz(e)aceanthrylene; D008748:Methylcholanthrene; C041193:benz(l)aceanthrylene; C037411:benz(j)aceanthrylene; D013866:Thioguanine