We have demonstrated the in vivo and in vitro formation of fatty acid conjugates of xenobiotics, such as 2-chloroethanol (2-CE), 2-bromoethanol (2-BE), pentachlorophenol, (PCP) and aniline. Futhermore, we have shown that the fatty acid conjugates, palmitoyl pentachlorophenol (PPCP) and 2- chloroethyl linoleate (2-CEL), are toxic to rat pancreas and liver, respectively. We now propose to study the extent of formation, dose- and time-dependence, and quantitation of fatty acid conjugates of 2-CE, 2-BE, PCP and aniline in liver and pancreas, as well as in other tissues of rats. Toxicity of these compounds will be assessed histopathologically and by organ function tests. Involvement of caboxyesterases in the synthesis and metabolism of fatty acid conjugates will also be studied. The enzymes which conjugate fatty acids to 2-CE, 2-BE, PCP and aniline have not yet been characterized. We have shown that the enzymes catalyzing the conjugation of 2-CE and 2-BE are present in relatively higher concentrations in pancreas and liver as compared to other tissues. Our preliminary studies also indicate that one of the pancreatic enzymes has some kinetic and structural similarities with fatty acid ethyl ester synthetase (FAEES), having approximately 38% homology at the N-terminal sequence. We will purify the conjugating enzymes to homogeneity from liver and pancreas. The primary and secondary structures, kinetic properties and substrate specificities of these enzymes will be determined and compared to those of FAEES isozymes. Antibodies raised against these enzymes will be used for their immunocytochemical localization in various tissues, and to study immunological interrelationship with FAEES isozymes. Fatty acid conjugates formed both in vitro and in vivo are found to be toxic. Our studies will lead to an understanding of how and by which enzymes these conjugates are formed and how they exert their toxicity. This information will be useful in preventing toxicity and/or devising therapies.
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