LIPID CONJUGATES OF XENOBIOTICS

描述(改编自调查者摘要)：为了 了解能够形成脂肪的外源生物的毒性机制 酸结合物，研究人员已经分离并鉴定了大鼠肝脏 脂肪酸乙酯合成酶(FAEEs)是一种参与 外源化合物与脂肪酸的偶联。他们的研究还表明 肝脏和胰腺中存在几种FAEs同工酶 S的FAEE在功能上是不同的。因此，这些调查人员 将从肝脏和肝脏中纯化并鉴定FAEE的各种同工酶 并通过表征它们的特征来建立它们之间的相互关系 结构和功能特性。FAEs的抑制剂和诱导剂将 也要确定(具体目标1)。脂肪酸偶联物的形成 两种模型化合物，甲醇和苯胺，将在体内和在 正常和FAEE抑制/诱导条件下的HepG2细胞(特异性 目标2)。苯胺脂肪酸偶联物的毒性机制 (脂肪酸苯胺)和甲醇(脂肪酸甲酯) 调查(具体目标3)。脂肪酸苯胺的潜在价值 诱导自身免疫及脂肪酸甲酯的作用机制(S) 抑制库普弗细胞功能(吞噬功能)是不明的，并将 通过对脂肪酸甲基代谢的研究来深入研究 库普弗细胞中的酯及其对能量产生的影响。 这个项目应该提供一个清楚的了解脂肪的形成。 外源化合物的酸结合物、参与这种结合物的酶以及 这种偶联物发挥其毒性的机制(S)。信息 从这些研究中获得的信息将有助于预防和/或设计 脂肪酸偶联物介导的毒性治疗。

DESCRIPTION (Adapted from the Investigator's Abstract): In order to understand the mechanism of toxicity of xenobiotics capable of forming fatty acid conjugates, the investigators have isolated and characterized rat liver fatty acid ethyl ester synthase (FAEES), a major enzyme involved in the conjugation of xenobiotics with fatty acids. their studies also indicate that there are several FAEES isozymes present in the liver, and pancreatic FAEES(s) is (are) functionally different. Therefore, these investigators will purify and characterize various isozymes of FAEES from the liver and pancreas and establish their interrelationship by characterizing their structural and functional properties. Inhibitors and inducers of FAEES will also be identified (Specific Aim 1). Formation of fatty acid conjugates of two model compounds, methanol and aniline, will be studied in vivo and in HepG2 cells under normal and FAEES inhibited/induced conditions (Specific Aim 2). The mechanisms of toxicity of fatty acid conjugates of aniline (fatty acid anilides) and methanol (fatty acid methyl esters) will be investigated (Specific Aim 3). The potential of fatty acid anilides to induce autoimmunity and the mechanism(s) by which fatty acid methyl esters inhibit Kupffer cell function (phagocytosis) is obscure, and will be thoroughly investigated by studying the metabolism of fatty acid methyl esters in Kupffer cells and their effect on energy production. This project should provide a clear understanding of the formation of fatty acid conjugates of xenobiotics, enzymes involved in such conjugation and the mechanism(s) by which such conjugates exert their toxicity. Information obtained from these studies will be useful in preventing and/or devising therapies for the toxicities mediated by fatty acid conjugates.