LIPID CONJUGATES OF XENOBIOTICS

了解导致毒性的机制 能够形成脂肪酸（FA）结合物的外源性物质， 表征了大鼠肝FA乙酯合成酶（FAEES）同工酶， 将外源性物质与脂肪酸结合。研究表明，胰腺和血浆 FAEES在结构和功能上与它们所表征的那些不同 在肝脏中。因此，在目标1中，他们将纯化和表征FAEES， 胰腺和血浆，并建立它们彼此之间的相互关系， 肝酶的结构和功能特性的比较。这些 将使用抑制剂（例如， 三邻甲苯基磷酸酯）和诱导剂（例如，苯巴比妥）。在目标2中， 将在肝癌细胞系中检查FA缀合物的相对形成 表达不同水平的参与常规氧化的酶 模型化合物甲醇和苯胺的代谢。在目标3中， 生物学上重要的FA结合的形成、动力学和酶学 功能化合物将在体内、体外和细胞中进行研究。 文化最后，在目的4中，研究了FA缀合物的毒性机制。 将对甲醇（FA甲酯）和苯胺（脂肪酸苯胺）进行评价 in vivo. FA甲酯抑制枯否细胞功能的机制 （吞噬作用）将通过研究它们的代谢和 影响能源生产。同样，FA甲基的胰腺毒性 将评价酯，沿着FA酰苯胺的评价，以诱导 自身免疫和相关机制。该项目可以提供一个明确的 了解外源性物质的FA缀合物的形成，酶 参与这一过程的机制和这种缀合物发挥 其毒性。这一信息可能对制定办法， 防止FA缀合物介导的毒性。

To understand the mechanism(s) responsible for toxicity of xenobiotics capable of forming fatty acid (FA) conjugates, the investigators characterized rat liver FA ethyl ester synthetase (FAEES) isozymes that conjugate xenobiotics to FAs. The studies indicate that pancreatic and plasma FAEES are structurally and functionally different from those they characterized in the liver. Therefore, in Aim 1, they will purify and characterize FAEES from pancreas and plasma and establish their interrelationships to each other and to the liver enzymes by comparing structural and functional properties. These relationships will be further characterized using inhibitors (e.g., tri-o-tolyphosphate) and inducers (e.g., phenobarbital) of FAESS. In Aim 2, the relative formation of FA conjugates will be examined in hepatoma cell lines expressing different levels of enzymes involved in the conventional oxidative metabolism of the model compounds methanol and aniline. In Aim 3, the formation, kinetics and enzymology of FA conjugation of biologically important functional compounds will be investigated in vivo and in vitro and in cell culture. Finally, in Aim 4, the mechanism of toxicity of FA conjugates of methanol (FA methyl esters) and aniline (fatty acid anilides) will be evaluated in vivo. The mechanism by which FA methyl esters inhibit Kupffer cell function (phagocytosis) will be thoroughly investigated by studying their metabolism and effect on energy production. Similarly, the pancreatic toxicity of FA methyl esters will be evaluated, along with the evaluation of FA anilides to induce autoimmunity, and associate mechanisms. The project may provide a clear understanding of the formation of FA conjugates of xenobiotics, the enzymes involved in this process and the mechanism(s) by which such conjugates exert their toxicity. This information may be important in devising approaches to prevent the toxicities mediated by FA conjugates.