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Sulfite enhancement of diolepoxide mutagenicity: the role of altered glutathione metabolism
Department of Pharmacology, Toxicology and Therapeutics and Center for Environmental and Occupational Health, University of Kansas Medical Center Kansas City, KS 66103, USA
Sulfur dioxide is a cocarcinogen for benzo[a] in the respiratory tract of rats and hamsters. Sulfur dioxide exists under physiological conditions as the sulfite ion. Sulfite enhances the mutagenic potency of (±-7r,8t-dihydroxy-9t,-10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) and 7r,8t-dihydroxy-9c10c-epoxy-7,8,9,10-tetrahydro benzo[a]pyrene (syn-BPDE) in Salmonella typhimurium strains TA98 and TA100. This enhancement of diolepoxide mutagenicity is observed with sulfite concentrations between 1 and 20 mM, and the concentration dependence is identical for the two diolepoxides. Half-maximal enhancement of mutagenicIty occurs at 
5 mM sulfite. Sulfite Is neither toxic nor mutagenic to the bacteria under these conditions. The enhancement of diolepoxide mutagenicity requires that the bacteria be exposed to sulfite prior to the addition of the diolepoxide. Simultaneous addition of sulfite and diolepoxide significantly decreases the enhancing effect, and addition 15 min after the diolepoxide virtually abolishes the effect. This is consistent with sulfite serving to increase the efficiency of processes leading to DNA modification by the diolepoxides, rather than some effect subsequent to DNA adduct formation. Direct evidence for this hypothesis was provided by detennining the effect of sulfite on mutagenicity and DNA bindingin TA98 using [3H]anti-BPDE. Exposure of the bacteria to 10 mM sulfite for 5 mm prior to the addition of the labeled mutagen led to as much as 170% increase in DNA binding levels relative to parallel incuhations without sulfite. Corresponding increases in mutagenicity were seen as well. As sulfite can affect the glutathioneiglutathione-.S-transferase systems, the primary cellular defense against BPDE, the effect of sulfite on these pathways in Salmonella was determined. When strain TA98 was treated with N-acetoxy-2-acetamido-fluorene, a direct-acting mutagen not scavenged by gluta thione, prior addition of 10 mM sulfite to the bacteria had no effect on resultant viability or mutagenicity. Assessment of the bacterial glutathione levels revealed that 10mM sulfite treatment results in an 82% decrease In the concentration of the cosubstrate. We were, however, unable to detect diolepoxide-glutathione conjugates In any of our inc Moreover, the presence of sulfite leads to significant trapping of the diolepoxide in the form of sulfonate derivatives. Based on these data, we conclude that the depletion of glutathione does Indeed play arole in the enhancement of diolepoxide mutagemcity in S.typhimurium. Our Inability to detect BPDE-glutathlone conjugates in these systems, however, and the observation of novel sulfite-dependent 13P11)E-derived products In these incuhations, suggests that ghjtathione depletion may not he the only mechanism involved in the enhancing effect.
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