Moran J H, Weise R, Schnellmann R G, Freeman J P, Grant D F
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham, Slot 638, Little Rock, Arkansas 72205-7199, USA.
Toxicol Appl Pharmacol. 1997 Sep;146(1):53-9. doi: 10.1006/taap.1997.8197.
Monoepoxides of linoleic acid (leukotoxin and isoleukotoxin) have been associated with a variety of pathophysiological diseases in humans including multiple organ failure. They also have been shown to be toxic when injected into experimental animals. Because leukotoxin and isoleukotoxin are excellent substrates for epoxide hydrolases, we tested the hypothesis that the diol metabolites are less toxic than the parent monoepoxides using the rabbit renal proximal tubule (RPT) suspension model. An equimolar mixture of the positional isomers of the methyl esters of leukotoxin and isoleukotoxin did not cause cell death to RPT cells at concentrations up to 1 mm using lactate dehydrogenase release as the endpoint. The corresponding diols, however, caused cell death in a time- and concentration-dependent manner beginning at 4 hr and reaching 42% cell death in 6 hr at 1 mm. Cell death was not due to oxidative stress since malondialdehyde content did not increase and the iron chelator deferoxamine and the antioxidant N,N'-diphenyl-1, 4-phenylenediamine were not cytoprotective. In contrast, cell death was associated with mitochondrial dysfunction with respiration decreasing 54% prior to the onset of cell death. Secondary to the mitochondrial dysfunction, the diols completely inhibited active Na+ transport within 30 min of addition. These results suggest that the in vivo toxicity and pathophysiology previously attributed to the monoepoxides of linoleic acid may be due to the diol metabolites.
亚油酸的单环氧化物（白细胞毒素和异白细胞毒素）与人类的多种病理生理疾病有关，包括多器官衰竭。它们注射到实验动物体内时也显示出毒性。由于白细胞毒素和异白细胞毒素是环氧水解酶的优良底物，我们使用兔肾近端小管（RPT）悬浮模型来检验二醇代谢产物比母体单环氧化物毒性更小的假设。以乳酸脱氢酶释放作为终点指标，白细胞毒素和异白细胞毒素甲酯的位置异构体等摩尔混合物在浓度高达1 mM时不会导致RPT细胞死亡。然而，相应的二醇以时间和浓度依赖性方式导致细胞死亡，从4小时开始，在1 mM时6小时内细胞死亡率达到42%。细胞死亡不是由于氧化应激，因为丙二醛含量没有增加，铁螯合剂去铁胺和抗氧化剂N，N'-二苯基-1，4-苯二胺没有细胞保护作用。相反，细胞死亡与线粒体功能障碍有关，在细胞死亡开始前呼吸作用下降了54%。继发于线粒体功能障碍，二醇在添加后30分钟内完全抑制了活性Na+转运。这些结果表明，先前归因于亚油酸单环氧化物的体内毒性和病理生理学可能是由于二醇代谢产物。
