LIPID CONJUGATES OF XENOBIOTICS

了解黄曲霉毒素的毒性作用机制(S) 能够形成脂肪酸(FA)结合物的外源生物，研究人员 大鼠肝脏脂肪酸乙酯合成酶(FAEEs)同工酶的特征 将外源物质与脂肪酸偶联。研究表明，胰腺和血浆 FAE在结构和功能上都不同于它们所描述的那些 在肝脏里。因此，在目标1中，他们将从 胰腺和血浆，并建立它们之间的相互关系和 通过比较肝酶的结构和功能特性。这些 将使用抑制物进一步表征关系(例如， 苯巴比妥)和诱导剂(如苯巴比妥)。在目标2中， 将在肝癌细胞系中检测FA结合物的相对形成 表达参与常规氧化的不同水平的酶 模型化合物甲醇和苯胺的代谢。在目标3中， 具有重要生物学意义的脂肪酸结合物的形成、动力学和酶学研究 功能化合物将在体内、体外和细胞内进行研究 文化。最后，在目标4中，探讨了黄曲霉毒素结合物的毒性机制。 将对甲醇(FA甲酯)和苯胺(脂肪酸苯胺)进行评估 在活体内。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 对能源生产的影响。类似地，甲酸对胰腺的毒性 将对酯进行评估，同时对FA苯胺进行评估以诱导 自身免疫和相关机制。该项目可能会提供一个明确的 对外源生物酶的FA偶联物形成的理解 参与这一过程以及这种共轭化合物发挥作用的机制(S 它们的毒性。这些信息在设计方法时可能很重要 预防FA结合物介导的毒性反应。

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.