GENOTOXICITY OF BENZO[A]PYRENE DERIVATIVES AND SULFITE

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Sulfur dioxide, a ubiquitous air pollutant and a component of tobacco smoke, is a cocarcinogen for benzo[a]pyrene (BP) in the respiratory tract. We have investigated effects of sulfite, the physiological form of sulfur dioxide, on the metabolism and the genotoxicity of BP metabolites. This proposal focuses on interactions of sulfite with 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and 7r,8t-dihydroxy-9t,10t-epoxy7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) to form isomeric bay-region BPT sulfonates. These derivatives, formed in high yield in incubations with either S. typhimurium tester strains or with hamster trachea in organ culture, represent a novel class of reactive intermediates. Although far more stable to hydrolysis than are bay-region diolepoxides, these sulfonates nevertheless bind covalently to DNA at levels comparable to those seen with the diolepoxides. Based on our findings, we have developed and will test the hypothesis that formation of genotoxic BPT sulfonates represents a mechanism by which sulfur dioxide enhances BP carcinogenicity. The overall goal of this application is to characterize the biochemical and biological factors affecting both the formation of BPT sulfonates and their biological activities. Chemical characterization will examine the reactivity of BPT sulfonates with DNA, RNA, and protein. Due to the importance of DNA modification in mutagenesis and carcinogenesis, the interactions of the sulfonates with DNA will be studied by both 32p-postlabeling and structural characterization of deoxynucleoside adducts. In all cases, behavior of the sulfonates will be compared with that of anti-BPDE. The ability of these BPT sulfonates to form in biological systems, and their effects on these systems will be examined using the V79 hamster lung cell line. V79 cells will be treated with anti-BPDE with and without sulfite, or with BPT sulfonates, and the resultant BP product profile and the induction of covalent binding to cellular macromolecules will be determined. Finally, the genotoxic activity of BPT sulfonates will be determined in the V79 system using selection for the hgprt phenotype. The primary aim of this project is to characterize the chemical and biological properties of BPT sulfonates, which represent a novel class of reactive intermediates. If these products are formed readily in intact mammalian cells, if they readily modify cellular nucleic acids, and if they exert genotoxic effects in this system, then a process consistent with the observed enhancing effect of sulfur dioxide on BP carcinogenesis will be established.