Our long-term goals are to study the mechanism(s) by which xenobiotic conjugates of lipids are formed and establish the contribution of these conjugates to the intrinsic toxicity of their parent xenobiotics. We propose to study the in vivo and in vitro formation of fatty acid and cholesterol conjugates of pentachlorophenol, chloroethanols and chloroacetic acids and also the compounds which lead to the formation of these chloroethanols and chloroacetic acid as metabolites. The xenobiotic conjugates formed will be isolated and purified using established chromatographic techniques (thin layer, gas, and high performance liquid chromatography) followed by structure elucidation using spectral techniques (ultraviolet, infrared, nuclear magnetic resonance and mass spectrometry). The toxicity of these conjugates will be characterized using morphological (histochemistry, electron microscopy) and biochemical parameters (organ function analysis using serum and target tissue enzymes) in rats. In addition, enzyme(s) involved in the formation and degradation of these conjugates will also be studied using standard protein chemistry methodologies such as enzyme assays, column chromatography, isoelectric focusing and chromatofocusing, electrophoresis, amino acid analysis, and sequencing. Although several lipid conjugates of xenobiotics have been identified within the last decade, both under in vitro and in vivo conditions, the information regarding their mechanism of formation and their contribution to the toxicity is virtually unknown. The proposed studies will lead to an understanding of how such conjugates are formed, their associated toxicity, and the enzymes involved in the formation and degradation of these conjugates.
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