Slim R, Hammock B D, Toborek M, Robertson L W, Newman J W, Morisseau C H, Watkins B A, Saraswathi V, Hennig B
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40506-0054, USA.
Toxicol Appl Pharmacol. 2001 Mar 15;171(3):184-93. doi: 10.1006/taap.2001.9131.
Selected dietary lipids may increase the atherogenic effects of environmental chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. We have shown previously that the omega-6 parent fatty acid, linoleic acid, or 3,3',4,4'-tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor agonist, independently can cause disruption of endothelial barrier function. Furthermore, cellular enrichment with linoleic acid can amplify PCB-induced endothelial cell dysfunction. We hypothesize that the amplified toxicity of linoleic acid and PCBs to endothelial cells could be mediated in part by cytotoxic epoxide metabolites of linoleic acid called leukotoxins (LTX) or their diol derivatives (LTXD). Exposure to LTXD resulted in a dose-dependent increase in albumin transfer across endothelial cell monolayers, whereas this disruption of endothelial barrier function was observed only at a high concentration of LTX. Pretreatment with the cytosolic epoxide hydrolase inhibitor 1-cyclohexyl-3-dodecyl urea partially protected against the observed LTX-induced endothelial dysfunction. Endothelial cell activation mediated by LTX and/or LTXD also enhanced nuclear translocation of the transcription factor NF-kappa B and gene expression of the inflammatory cytokine IL-6. Inhibiting cytosolic epoxide hydrolase decreased the LTX-mediated induction of both NF-kappa B and the IL-6 gene, whereas the antioxidant vitamin E did not block LTX-induced endothelial cell activation. Most importantly, inhibition of cytosolic epoxide hydrolase blocked both linoleic acid-induced cytotoxicity, as well as the additive toxicity of linoleic acid plus PCB 77 to endothelial cells. Interestingly, cellular uptake and accumulation of linoleic acid was markedly enhanced in the presence of PCB 77. These data suggest that cytotoxic epoxide metabolites of linoleic acid play a critical role in linoleic acid-induced endothelial cell dysfunction. Furthermore, the severe toxicity of PCBs in the presence of linoleic acid may be due in part to the generation of epoxide and diol metabolites. These findings have implications in understanding interactive mechanisms of how dietary fats can modulate dysfunction of the vascular endothelium mediated by certain environmental contaminants.
某些膳食脂质可能通过交叉放大机制增强环境化学物质（如多氯联苯（PCBs））的致动脉粥样硬化作用，进而导致血管内皮功能障碍。我们之前已经表明，ω-6母体脂肪酸亚油酸或芳烃（Ah）受体激动剂3,3',4,4'-四氯联苯（PCB 77）能够独立引起内皮屏障功能的破坏。此外，细胞内亚油酸的富集能够增强PCB诱导的内皮细胞功能障碍。我们推测，亚油酸和PCBs对内皮细胞的毒性增强可能部分是由亚油酸的细胞毒性环氧化代谢产物白细胞毒素（LTX）或其二醇衍生物（LTXD）介导的。暴露于LTXD会导致白蛋白跨内皮细胞单层转运呈剂量依赖性增加，而只有在高浓度的LTX时才会观察到这种内皮屏障功能的破坏。用胞质环氧化物水解酶抑制剂1-环己基-3-十二烷基脲预处理可部分预防所观察到的LTX诱导的内皮功能障碍。由LTX和/或LTXD介导的内皮细胞活化还增强了转录因子NF-κB的核转位以及炎性细胞因子IL-6的基因表达。抑制胞质环氧化物水解酶可降低LTX介导的NF-κB和IL-6基因的诱导，而抗氧化剂维生素E并不能阻断LTX诱导的内皮细胞活化。最重要的是，抑制胞质环氧化物水解酶可阻断亚油酸诱导的细胞毒性以及亚油酸加PCB 77对内皮细胞的相加毒性。有趣的是，在存在PCB 77的情况下，亚油酸的细胞摄取和积累明显增强。这些数据表明，亚油酸的细胞毒性环氧化代谢产物在亚油酸诱导的内皮细胞功能障碍中起关键作用。此外，在亚油酸存在下PCBs的严重毒性可能部分归因于环氧化物和二醇代谢产物的产生。这些发现对于理解膳食脂肪如何调节由某些环境污染物介导的血管内皮功能障碍的相互作用机制具有重要意义。
