Bacterial mutagenicity of the three isomeric dicyclopenta-fused pyrenes: the effects of dicyclopenta topology

• Published in: Mutation research. Genetic toxicology and environmental mutagenesis 2004-04, Vol.559 (1-2), p.105-119
• Main Authors: Otero-Lobato, Marı́a José, Jenneskens, Leonardus W, Seinen, Willem
• Format: Article
• Language: English
• Subjects: Bacterial mutagenicity; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Medical sciences; Non-alternant cyclopenta-fused PAH; Salmonella typhimurium; Salmonella typhimurium TA98; Semi-empirical AM1 calculations; Toxicology
• ISSN: 1383-5718; 1879-3592
• DOI: 10.1016/j.mrgentox.2004.01.005

Cyclopenta[cd]pyrene (1) and its congeners dicyclopenta[cd,mn]- (2), dicyclopenta[cd,fg]- (3), dicyclopenta[cd,jk]pyrene (4), which were all identified as constituents of combustion exhausts, as well as their partially hydrogenated derivatives 3,4-dihydrocyclopenta[cd]- (5), 1,2,4,5-tetrahydrodicyclopenta[cd,mn]- (6), 5,6,7,8-tetrahydrodicyclopenta[cd,fg]- (7) and 1,2,6,7-tetrahydrodicyclopenta[cd,jk]pyrene (8), were assayed for mutagenicity in the Salmonella typhimurium strain TA98 using different concentrations of microsomal protein in the metabolic activation system (S9-mix, with S9-fraction from liver of Aroclor-1254-treated rats: 2, 4 and 10% (v/v), respectively). Whereas a positive mutagenic response is found for 1–4 in the presence of S9-mix, 5–8 exert no mutagenicity either with or without S9-mix. Since for 1–4 the highest response is observed with S9-mix 2% (v/v) instead of the standard 4% (v/v), a one-step activation pathway, i.e. epoxidation of the five-membered ring olefinic bonds, appears to be operational. Surprisingly, 3 and, to a lesser extent, 2 (11.7 versus 4.2 His revertants/nmol) also give a positive response in the absence of S9-mix. Hence, 2 and 3 are expected to contribute to the direct-acting mutagenicity of the non-polar fraction of combustion exhausts. Presumably for the direct-acting mutagenicity one-electron transfer processes play a role in bioactivation. The experimental observations are supported by semi-empirical AM1 calculations on the possible ultimate metabolites, i.e. mono-epoxides (2a–4a), cis-di-epoxides (2b–4b) and trans-di-epoxides (2c–4c) and the related mono-hydroxy carbocations (2d–4d and 2e–4e), and the radical anions 1−–4−.