Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase
Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase
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DOI：
10.1038/nm0597-562
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发表时间：
1997-05-01
期刊：
影响因子：
82.9
通讯作者：
Hammock, BD
中科院分区：
文献类型：
--
作者：
Moghaddam, MF;Grant, DF;Hammock, BD
白细胞毒素是由白细胞产生的一种亚油酸酸氧化物，与严重烧伤患者的多器官功能衰竭和成人呼吸窘迫综合征有关。据报道，当静脉注射到动物体内时，白细胞毒素是有毒的。在此，我们报告说，这种脂质是没有，直接在至少两个体外系统的细胞毒性。使用杆状病毒表达系统，我们证明，白细胞毒素只有在环氧化物水解酶的存在下是细胞毒性的。此外，证明二醇代谢物对肺泡上皮细胞具有毒性，表明二醇在白细胞毒素相关呼吸系统疾病中具有关键作用。体内数据也支持白细胞毒素二醇的毒性。我们第一次证明了可溶性环氧化物水解酶可以将环氧化物生物活化为具有明显细胞毒性的二醇。因此，白细胞毒素应被视为一种原毒素，对应于毒性更大的二醇。这显然对设计新的临床干预措施有影响。
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.