Many chemicals and their corresponding cysteine S-conjugates, which are intermediates in the mercapturic acid pathway, are metabolized in vivo to cysteine S-conjugate sulfoxides and/or N-acetylcysteine S-conjugate sulfoxides. Previous work in this laboratory provided the first evidence for the involvement of flavin-containing monooxygenases (FMOs) in cysteine conjugate S-oxidase activities of rat and rabbit liver and kidney. Sulfoxidation of the cysteine S-conjugates of the industrial solvents trichloroethylene and tetrachloroethylene has also been shown to yield electrophilic sulfoxides that may contribute to the nephrotoxicity and carcinogenicity of these chemicals. Because there are currently five known FMO isoforms (identified as FMO1-5) and some of these isoforms exhibit gender- and tissue- dependent expression, the broad objective of the proposed is to characterize the relative contributions of FMO isoforms in the metabolism and toxicity of cysteine S-conjugates. Similar studies will be conducted with methionine and selenomethionine, structural analogues of cysteine S-conjugates which we have also identified as FMO substrates and are known to cause toxicity when given to animals at high levels. Specific experimental objectives are: 1) To isolate and characterize the substrate selectivities of rat hepatic and renal FMO3 and FMO4; 2) To characterize species-, gender-, and age-dependent expression of FMO4, and provide further characterization of FMO1 and FMO3 expression in liver and kidney; 3) To quantitate in vivo FMO activity in rats and mice using cysteine S-conjugates; 4) To characterize the toxicity associated with cysteine S-conjugate sulfoxides and selenomethionine oxide. The proposed studies will allow for a better understanding of FMO expression and the mechanisms of toxicity of cysteine S-conjugates and related chemical, leading to a more accurate assessment of human risk to these chemicals.
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