LIPID CONJUGATES OF XENOBIOTICS

描述（改编自研究者摘要）：为了 了解能够形成脂肪酸的外源性物质的毒性机制， 酸共轭物，研究人员已经分离并表征了大鼠肝脏 脂肪酸乙酯合成酶（FAEES），一种参与脂肪酸合成的主要酶， 异生物质与脂肪酸的缀合。 他们的研究还表明， 在肝脏和胰腺中存在几种FAEES同工酶， FAEES在功能上不同。 因此，这些调查人员 将纯化和表征来自肝脏的FAEES的各种同工酶， 胰腺，并通过表征它们的 结构和功能特性。 FAEES的抑制剂和诱导剂将 具体目标（1）。 脂肪酸缀合物的形成 两个模型化合物，甲醇和苯胺，将在体内和体内进行研究， 正常和FAEES抑制/诱导条件下的HepG 2细胞（特异性 目标2）。 苯胺脂肪酸共轭物的毒性机制 脂肪酸甲酯（脂肪酸酰苯胺）和甲醇（脂肪酸甲酯）将被 具体目标（3）。 脂肪酸酰苯胺的潜力， 诱导自身免疫和脂肪酸甲酯 抑制枯否细胞功能（吞噬作用）是模糊， 通过研究脂肪酸甲酯的代谢， Kupffer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晰的认识，形成脂肪 外源性物质的酸缀合物、参与这种缀合的酶以及 这类缀合物发挥其毒性的机制。 信息 从这些研究中获得的信息将有助于预防和/或设计 治疗由脂肪酸缀合物介导的毒性。

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.