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.

The structures of alpha-naphthoflavone (ANF) dihydrodiols formed by uninduced and induced rat liver microsomes are identified by conversion of the metabolically formed ANF-dihydrodiols to the corresponding phenols. Comparison of these phenols with synthetic standards provides an unambiguous method for structural identification. The results of these studies are that hepatic microsomes from uninduced or phenobarbital, Aroclor-1254, 3-methylcholanthrene, or 5,6-benzoflavone induced Sprague-Dawley or Charles River CD rats each produce a major and a minor ANF-dihydrodiol identified as ANF-7,8-dihydrodiol and ANF-5,6-dihydrodiol, respectively.

Initial studies on the mutagenicity and metabolism of a novel cyclopenta-PAH, benz[j]aceanthrylene, are reported in the Salmonella bacterial system. The spectrum of activity of benz[j]aceanthrylene over the 5 Ames tester strains is similar to that of benzo[a]pyrene, and the dose-response curves for strain TA98 are comparable. Like other biologically active PAH, benz[j]aceanthrylene is a frame-shift mutagen requiring metabolic activation. An interesting feature of the S9 dependence of activity is the low concentration (≅10-fold smaller than for benzo[a]pyrene) at which optimal activity is observed. The 1,2-dihydro-1,2-diol (product of metabolism of the cyclopenta-ring) appears to be the predominant metabolite, and implicates the 1,2-oxide as the ultimate mutagenic species.

alpha-Naphthoflavone (ANF) inhibits beta-naphthoflavone-induced rat liver microsomal benzo(a)pyrene metabolism and is transformed by these microsomes into alpha-naphthoflavone metabolites. We determined the inhibitory effect on benzo(a)pyrene (B(a)P) metabolism of several of these metabolites and of 6-methoxy-ANF, using beta-naphthoflavone-induced rat liver microsomes. 9-Hydroxy-ANF was the most active inhibitor (I50 = 1.47 microM) and was metabolized from ANF by these hepatic microsomes in concentrations which are inhibitory. Therefore, 9-hydroxy-ANF a microsomal metabolite of ANF, may play a role in the inhibition of B(a)P oxidation by ANF.

Annals of the New York Academy of SciencesVolume 349, Issue 1 p. 247-263 CARCINOGEN METABOLISM IN RAT LIVER CELL CULTURE*,† Stephen Nesnow, Stephen Nesnow Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711 Request for reprints should be addressed to Dr. Nesnow.Search for more papers by this authorJoellen Huisingh, Joellen Huisingh Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorHinda Bergman, Hinda Bergman Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorRobert Easterling, Robert Easterling Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorJeff Inmon, Jeff Inmon Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorLeon King, Leon King Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorMary S. Morris, Mary S. Morris Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorKatherine Williams, Katherine Williams Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorBetty Hyatt, Betty Hyatt Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this authorLinda Montgomery, Linda Montgomery Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this authorClaire Cudak, Claire Cudak Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this author Stephen Nesnow, Stephen Nesnow Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711 Request for reprints should be addressed to Dr. Nesnow.Search for more papers by this authorJoellen Huisingh, Joellen Huisingh Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorHinda Bergman, Hinda Bergman Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorRobert Easterling, Robert Easterling Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorJeff Inmon, Jeff Inmon Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorLeon King, Leon King Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorMary S. Morris, Mary S. Morris Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorKatherine Williams, Katherine Williams Genetic Toxicology Division Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711Search for more papers by this authorBetty Hyatt, Betty Hyatt Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this authorLinda Montgomery, Linda Montgomery Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this authorClaire Cudak, Claire Cudak Northrop Services, Inc. Research Triangle Park, North Carolina 27711Search for more papers by this author First published: September 1980 https://doi.org/10.1111/j.1749-6632.1980.tb29531.xCitations: 10 † A preliminary account of this work has been reported at the 29th Annual Meeting of the Tissue Culture Association, Denver, Colorado, June 1978. ‡ The abbreviations used are: B(a)P: benzo(a)pyrene; pre-9,10-diol: all radioactivity eluted prior to 9,10-diol; 9,10-diol: 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene; 4,5-diol: 4,5-dihydro-4,5-dihydroxybenzo-(a)pyrene; 7,8-diol: 7,8-dihydro-7,8-dihydroxybcnzo(a)pyrene; 9-phenol: 9-hydroxybenzo-(a)pyrene; 3-phenol: 3-hydroxybenzo(a)pyrene. 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