Moghaddam M F, Grant D F, Cheek J M, Greene J F, Williamson K C, Hammock B D
DuPont Agricultural Products, Wilmington, Delaware 19880-0402, USA.
Nat Med. 1997 May;3(5):562-6. doi: 10.1038/nm0597-562.
Leukotoxin is a linoleic acic oxide produced by leukocytes and has been associated with the multiple organ failure and adult respiratory distress syndrome seen in some severe burn patients. Leukotoxin has been reported to be toxic when injected into animals intravenously. Herein, we report that this lipid is not directly cytotoxic in at least two in vitro systems. Using a baculovirus expression system we demonstrate that leukotoxin is only cytotoxic in the presence of epoxide hydrolases. In addition, it is the diol metabolite that proves toxic to pulmonary alveolar epithelial cells, suggesting a critical role for the diol in leukotoxin-associated respiratory disease. In vivo data also support the toxicity of leukotoxin diol. For the first time we demonstrate that soluble epoxide hydrolase can bioactivate epoxides to diols that are apparently cytotoxic. Thus leukotoxin should be regarded as a protoxin corresponding to the more toxic diol. This clearly has implications for designing new clinical interventions.
白细胞毒素是一种由白细胞产生的亚油酸环氧化物，与一些严重烧伤患者出现的多器官功能衰竭和成人呼吸窘迫综合征有关。据报道，将白细胞毒素静脉注射到动物体内时具有毒性。在此，我们报告这种脂质在至少两种体外系统中并非直接具有细胞毒性。利用杆状病毒表达系统，我们证明白细胞毒素仅在环氧水解酶存在的情况下具有细胞毒性。此外，证明对肺泡上皮细胞有毒性的是二醇代谢物，这表明二醇在白细胞毒素相关的呼吸道疾病中起关键作用。体内数据也支持白细胞毒素二醇的毒性。我们首次证明可溶性环氧水解酶可将环氧化物生物激活为明显具有细胞毒性的二醇。因此，白细胞毒素应被视为一种对应于毒性更强的二醇的原毒素。这显然对设计新的临床干预措施具有重要意义。
