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首页> 外文学位 >In vitro examination of the cytotoxic and cytoprotective mechanisms of linoleic acid, cis-epoxyoctadecenoic acids, and dihydroxyoctadecenoic acids in cellular and mitochondrial models.
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In vitro examination of the cytotoxic and cytoprotective mechanisms of linoleic acid, cis-epoxyoctadecenoic acids, and dihydroxyoctadecenoic acids in cellular and mitochondrial models.

机译：在细胞和线粒体模型中对亚油酸，顺式环氧十八烯酸和二羟基十八烯酸的细胞毒性和细胞保护机制进行体外检查。

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摘要

The toxicological significance of linoleic acid metabolism to the corresponding linoleic acid monoepoxides (EOAs) and diols (DHOAs) has been the subject of considerable research for approximately 15 years. However, the use of different fatty acid derivatives, as well as, different in vivo and in vitro models has made it difficult to make unifying conclusions about the overall importance of this metabolic pathway. The research presented in this dissertation is specifically designed to clarify discrepancies in current literature and to test the hypothesis: “Metabolism of linoleic acid to EOAs and DHOAs via extrahepatic cytochrome P450s and soluble epoxide hydrolase, respectively, represents an activation pathway which can explain many of pathological and cytoprotective properties of linoleic acid.” We tested the cytotoxic properties of these fatty acid metabolites in two different mammalian models, rabbit renal proximal tubules (RPT) and rabbit renal cortical mitochondria (RCM), and compared these results to an insect in vitro model, Sf-21 cells. The mechanism of toxicity for linoleic acid and the EOAs in rabbit RPT and RCM is mediated through the uncoupling of oxidative phoshphorylation. Of the tested metabolites, the DHOAs are the least toxic in rabbit RPT and RCM. These data suggest that the formation of EOAs and DHOAs is a detoxification pathway, and we have characterized human P450s (CYP2J2 and CYP2E1) which could be involved in this detoxification pathway. In contrast to the mammalian systems, the DHOAs appear to be the most toxic in Sf-21 cells and specifically inhibit the electron transport chain. Linoleic acid and the EOAs also uncouple oxidative phosphorylation in Sf-21 cells; however, these effects are transient in this model. In addition to studying the cytotoxic properties of these fatty acid metabolites, we examined the possibility that these compounds are produced in vivo as a protective response. Linoleic acid is a cytoprotective agent in rabbit RPT exposed to mitochondrial toxicants, and its cytoprotective mechanism occurs during the late phase of necrotic cell death and prevents the influx of extracellular chloride. Consistent with our toxicity data, metabolism of linoleic acid to the EOAs or DHOAs produces compounds which are not as cytoprotective as linoleic acid.
机译：亚油酸代谢对相应的亚油酸单环氧化物（EOA）和二醇（DHOAs）的毒理学意义已成为大约15年研究的主题。但是，使用不同的脂肪酸衍生物以及不同的体内和体外模型使得很难就这种代谢的总体重要性做出统一的结论。途径。本论文中提出的研究专门用于澄清当前文献中的差异并检验以下假设：亚油酸的病理和细胞保护特性。”我们在两种不同的哺乳动物模型（兔子肾近端小管（RPT）和兔子肾皮质线粒体（RCM））中测试了这些脂肪酸代谢物的细胞毒性，并将这些结果与昆虫的“斜体”体外模型进行了比较， Sf-21细胞。兔RPT和RCM对亚油酸和EOAs的毒性机制是通过氧化磷酸化的解偶联来介导的。在测试的代谢产物中，DHOA对兔子RPT和RCM的毒性最小。这些数据表明EOAs和DHOA的形成是排毒途径，并且我们已经表征了可能参与此排毒途径的人P450（CYP2J2和CYP2E1）。与哺乳动物系统相反，DHOA在Sf-21细胞中似乎最具毒性，并特别抑制电子传输链。亚油酸和EOAs还可以使Sf-21细胞中的氧化磷酸化解偶联。但是，这些影响在此模型中是短暂的。除了研究这些脂肪酸代谢产物的细胞毒性外，我们还研究了这些化合物在体内“产生”的可能性，作为保护性反应。亚油酸是暴露于线粒体有毒物质的兔RPT中的一种细胞保护剂，其细胞保护机制发生在坏死细胞死亡的晚期，并阻止细胞外氯化物的流入。与我们的毒性数据一致，亚油酸代谢成EOAs或DHOA所产生的化合物对细胞的保护作用不如亚油酸。

著录项

  • 作者

    Moran, Jeffery Harris.;

  • 作者单位

    University of Arkansas for Medical Sciences.;

  • 授予单位 University of Arkansas for Medical Sciences.;
  • 学科 Health Sciences Toxicology.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 268 p.
  • 总页数 268
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学（毒理学）;分子遗传学;
  • 关键词

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