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MUTAGENICITY IN SALMONELLA OF SULFUR-CONTAINING POLYCYCLIC AROMATIC HETEROCYCLES AND THEIR DIHYDRODIOL DERIVATIVES
Citation:
SWARTZ, C., S. NESNOW, H. C. SIKKA, AND S. KUMAR. MUTAGENICITY IN SALMONELLA OF SULFUR-CONTAINING POLYCYCLIC AROMATIC HETEROCYCLES AND THEIR DIHYDRODIOL DERIVATIVES. Presented at The 9th International Conference on Environmental Mutagens, and the 36th Annual Meeting of the Environmental Mutagen Society, San Francisco, CA, September 03, 2005.
Description:
Polycyclic aromatic sulfur heterocycles (PASH) are common constituents of cigarette smoke, fossil fuel-derived materials, and their combustion byproducts. Many PASH are known mutagens and carcinogens. However, unlike their nonsulfur-containing counterparts, relatively little is known of their mechanism of action. We synthesized dihydrodiol and sulfone derivatives of benzo[c]phenanthrene (B[c]Ph) and two 5-ringed, thiophene-fused phenanthrenes and tested their mutagenicity in the Salmonella (Ames) plate-incorporation assay in strains TA98 and TA100. The goal of the study was to examine the influence of the presence and position of the sulfur heteroatom on the mutagenic activity of B[c]Ph and to deduce the nature of the possible active intermediates. With the exception of phenantliro[3, 4-b]thiophene sulfone, all of the compounds tested were weak mutagens in TA98 (<20 rev/�g). The sulfone itself was the most potent compound in strain TA100 (~1000 rev/�g), which was approximately twice that of benzo[a]pyrene. Phenanthro[3,4-b]thiophene, a compound with the sulfur distal to the angular benzo-ring of B[c]Ph, was 10-fold more mutagenic than its carbocyclic analog B[c]Ph (580 vs. 54 rev/�g). The mutagenic activity of phenanthro[4, 3�b]thiophene, a compound with the sulfur proximal to the angular benzo-ring, was markedly reduced compared to that of B[c]Ph. Not surprisingly, the benzo-ring 3,4�dihydrodiol of B[c]Ph, which induced 250 rev/�g, was 5-fold more potent than B[c]Ph. Likewise, the analogous dihydrodiol of pheanthro[4,3-b]thiophene induced 240 rev/�g, which was 34-fold more potent than its parent compound. In contrast, the dihydrodiol of phenanthro[3,4-b]thiophene was ~7-fold less mutagenic than its parent compound. The K-region dihydrodiols showed little or no mutagenicity. These data suggest that PASH are potent base substitution mutagens, and may contribute significantly to the mutagenicity of tobacco smoke and industrial and vehicular emissions. The possibility that different phenanthrothiophenes may be activated through different mechanisms is currently under investigation. [HCS and SK supported, in part, by Philip Morris USA, Inc