LIPID CONJUGATES OF XENOBIOTICS

我们已经证明了在体内和体外形成的脂肪酸 外源性物质的缀合物，例如2-氯乙醇（2-CE）、2-溴乙醇 （2-BE）、五氯苯酚（PCP）和苯胺。福伯，我们已经证明了 脂肪酸共轭物，棕榈酰五氯苯酚（PPCP）和2- 氯乙基亚油酸酯（2-CEL）对大鼠胰腺和肝脏有毒， 分别 我们现在建议研究形成的程度、剂量和 时间依赖性和2-CE，2-BE， 五氯苯酚和苯胺在肝脏和胰腺，以及其他组织中的 大鼠这些化合物的毒性将通过组织病理学评估 和器官功能测试。羧酸酯酶参与 还将研究脂肪酸缀合物的合成和代谢。 将脂肪酸与2-CE、2-BE、PCP和苯胺结合的酶 尚未被定性。 我们已经证明， 催化2-CE和2-BE的缀合存在于相对 胰腺和肝脏中的浓度高于其他组织。 我们的初步研究还表明 与脂肪酸乙酯具有某些动力学和结构相似性 合成酶（FAEES），在N-末端具有约38%的同源性 顺序我们将纯化结合酶至同质， 肝脏和胰腺 一级和二级结构，动力学 这些酶的性质和底物特异性将是 并与FAEES同工酶进行比较。产生的抗体 针对这些酶将用于其免疫细胞化学 定位于各种组织，并研究免疫学 与FAEES同工酶的相互关系。 发现在体外和体内形成的脂肪酸缀合物是 有毒 我们的研究将使我们了解如何以及通过何种方式 酶这些共轭物的形成和它们如何发挥其毒性。 这些信息将有助于预防毒性和/或设计 治疗

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.