In common with many other drugs and xenobiotics, furosemide and ipomeanol (substituted furans) are metabolized to reactive intermediates that covalently bind to protein. The extent of binding correlated with hepatic necrosis in experimental animals. In contrast to many xenobiotics yielding electrophilic metabolites (including the structural analogue 2-furamide), no toxic dose threshold for glutathione is observed. The proposed research seeks to elucidate the underlying principles involved in these differences between electrophilic reactive metabolites. Thus, the differences in properties may be attributable to differences in the """"""""hardness"""""""" of electrophilicity of the metabolites or to the extent and nature of their interaction with glutathione transferases. Further understanding is dependent on the structural characterization of the adducts formed between the reactive metabolites and glutathione, alternate nucleophiles or cellular proteins. It is proposed to develop and apply tandem mass spectrometry to the characterization of these adducts. The mass spectrometric technique will be optimized with-respect to both ion production during fast atom bombardment and to collisionally activated dissociation of parent ions. The methods so developed are expected to have wide applicability. The elucidation of the structures of the adduct formed by reactive metabolites of substituted furans will contribute to a broader understanding of electrophilic drug/molecule interactions necessary for the interpretation of the mechanism and significance of alkylation events during the development of new drugs and the study of drug- induced tissue lesions.
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