Analysis of the cytotoxic properties of linoleic acid metabolites produced by renal and hepatic P450s
Analysis of the cytotoxic properties of linoleic acid metabolites produced by renal and hepatic P450s
复制标题
DOI：
10.1006/taap.2000.9053
复制
发表时间：
2000-11-01
影响因子：
3.8
通讯作者：
Grant, DF
中科院分区：
文献类型：
--
作者：
Moran, JH;Mitchell, LA;Grant, DF
亚油酸的细胞色素P450环氧化产生生物活性代谢物，这些代谢物与许多经常导致急性肾功能衰竭的病理状况有关。在本研究中，我们评估了特异性细胞色素p450产生亚油酸单环氧化物的能力。然后，我们在兔肾近端小管模型中测试了亚油酸、亚油酸单环氧化物和相应的二醇的细胞毒性。CYP1A2、CYP2E1、CYP2J2、CYP2J3、CYP2J5和CYP2J9代谢亚油酸的速率与花生四烯酸相当，主要产物为亚油酸单环氧化物。细胞毒性研究表明，亚油酸、亚油酸单环氧化物和相应的二醇在病理相关浓度（100-500 muM）下具有毒性。浓度依赖性研究表明，亚油酸和单环氧亚油酸毒性最大，并在细胞死亡前诱导线粒体功能障碍。已知的细胞保护剂可以阻止与线粒体功能障碍和氧化应激相关的细胞死亡，但不能阻止亚油酸和亚油酸单环氧化物诱导的细胞死亡。本研究表明，CYP1和CYP2基因家族中的p450将亚油酸代谢为亚油酸单环氧化物，而单环氧化物和亚油酸在不引起氧化应激的情况下破坏线粒体功能。(C) 2000年学术出版社。
Cytochrome P450 epoxidation of linoleic acid produces biologically active metabolites which have been associated with many pathological conditions that often lead to acute renal failure. In the present study, we evaluated the ability of specific cytochrome P450s to produce linoleic acid monoepoxides. We then tested the cytotoxic properties of linoleic acid, linoleic acid monoepoxides, and corresponding diols in a rabbit renal proximal tubule model. CYP1A2, CYP2E1, CYP2J2, CYP2J3, CYP2J5, and CYP2J9 metabolized linoleic acid at rates comparable to arachidonic acid and produced linoleic acid monoepoxides as major products. Cytotoxicity studies showed that linoleic acid, linoleic acid monoepoxides, and corresponding diols are toxic at pathologically relevant concentrations (100-500 muM). Concentration-dependent studies showed that linoleic acid and linoleic acid monoepoxides are the most toxic and induce mitochondrial dysfunction prior to cell death. Cytoprotectants known to block cell death associated with mitochondrial dysfunction and oxidative stress did not prevent cell death induced by linoleic acid and linoleic acid monoepoxides. This study shows that P450s in the CYP1 and CYP2 gene families metabolize linoleic acid to linoleic acid monoepoxides and that the monoepoxides, as well as linoleic acid, disrupt mitochondrial function without causing oxidative stress. (C) 2000 Academic Press.