This proposal is aimed at establishing the role of the gut microflora in the toxication/detoxication of S-conjugates in mammals. We use the term S-conjugates to include a variety of sulfur-containing metabolites derived from the biotransformation of xenobiotics. We have shown that rat intestinal microflora contain the enzyme thiol methyltransferase and sulfoxide reductase. These microbial enzymes may be important components in the overall balance of excretion/reabsorption of organosulfur metabolites of lipophilic xenobiotics. We have also shown that some aryl sulfoxides are direct acting mutagens in the Salmonella reversion assay. Some specific research goals are as follows. 1) To develop sensitive assays for thiol methyltransferase and sulfoxide reductase in whole microbial cells. 2) To use these techniques for the identification of mammalian gut microorganisms active in these reactions especially with polychlorinated biphenyl derivatives likely to be involved in enterohepatic circulation. 3) To study the properties of xenobiotic thiol methyltransferase in selected species of gut microflora. 4) To characterize the sulfoxide reductase of gut microflora, and establish its specificity and stereoselectivity for xenobiotic sulfoxides versus common sulfoxides such as dimethylsulfoxide and methionine sulfoxide. 5) To use the Salmonella reversion test to quantitate the mutagenicity of xenobiotic thiols, and their methylthio-, methylsulfoxyl- and methylsulfonyl-derivatives. 6) The metabolic activation/deactivation of these sulfur compounds in Salmonella tester strains and Escherichia coli, as a representative mammalian gut microorganism, and mammalian S-9 fractions used in the reversion tests will be studied to determine why certain organic sulfoxides act as direct mutagens.
