Morisseau C, Goodrow M H, Dowdy D, Zheng J, Greene J F, Sanborn J R, Hammock B D
Department of Entomology, University of California, Davis, CA 95616, USA.
Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8849-54. doi: 10.1073/pnas.96.16.8849.
The soluble epoxide hydrolase (sEH) plays a significant role in the biosynthesis of inflammation mediators as well as xenobiotic transformations. Herein, we report the discovery of substituted ureas and carbamates as potent inhibitors of sEH. Some of these selective, competitive tight-binding inhibitors with nanomolar K(i) values interacted stoichiometrically with the homogenous recombinant murine and human sEHs. These inhibitors enhance cytotoxicity of trans-stilbene oxide, which is active as the epoxide, but reduce cytotoxicity of leukotoxin, which is activated by epoxide hydrolase to its toxic diol. They also reduce toxicity of leukotoxin in vivo in mice and prevent symptoms suggestive of acute respiratory distress syndrome. These potent inhibitors may be valuable tools for testing hypotheses of involvement of diol and epoxide lipids in chemical mediation in vitro or in vivo systems.
可溶性环氧化物水解酶（sEH）在炎症介质的生物合成以及外源性物质的转化过程中发挥着重要作用。在此，我们报告了取代脲和氨基甲酸酯作为sEH强效抑制剂的发现。其中一些具有纳摩尔K(i)值的选择性、竞争性紧密结合抑制剂与同源重组小鼠和人sEH进行了化学计量相互作用。这些抑制剂增强了反式氧化芪（作为环氧化物具有活性）的细胞毒性，但降低了白细胞毒素（通过环氧化物水解酶激活为其有毒二醇）的细胞毒性。它们还降低了小鼠体内白细胞毒素的毒性，并预防了提示急性呼吸窘迫综合征的症状。这些强效抑制剂可能是用于测试二醇和环氧化物脂质在体外或体内系统化学介导中所涉及假设的有价值工具。
