Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase
Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase
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DOI：
10.1194/jlr.m009639
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发表时间：
2011-04-01
影响因子：
6.5
通讯作者：
Arand, Michael
中科院分区：
文献类型：
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作者：
Cronin, Annette;Decker, Martina;Arand, Michael
肝氧素是通过12-脂氧合酶途径从花生四烯酸衍生的脂质信号分子。这些反式环氧羟基类二十烷酸在多种生理过程中发挥作用，包括炎症、神经传递和皮肤屏障功能的形成。哺乳动物肝氧素水解酶，部分纯化的大鼠肝脏，早期已报道降解肝氧素三羟喹啉。在此，我们报道肝中的hepoxilin水解主要由可溶性环氧化物水解酶（sEH）催化：i）纯化的哺乳动物sEH水解hepoxilin A（3）和B-3，V-max为0.4-2.5 μ mol/mg/min; ii）高度选择性的sEH抑制剂N-金刚烷基-N '-环己基脲和12-环己基脲。（3-金刚烷-1-基-脲基）十二烷酸大大减少了小鼠肝脏制备物中的肝氧素水解; iii）在来自sEH（-/-）小鼠的肝脏制备物中肝氧素水解酶活性被消除;和iv）与野生型动物相比，sEH（-/-）小鼠的肝匀浆显示肝氧素的基础水平升高，但trioxilins的水平降低。我们得出结论，sEH与先前报道的肝氧素水解酶相同。这具有特别的生理相关性，因为sEH由于其在重要的脂质信号传导分子如环氧二十碳三烯酸的水解中的主要作用而成为新的药物靶标。sEH抑制剂可能对肝氧素信号传导具有不期望的副作用。克罗宁，A.，M.德克尔和M.阿兰哺乳动物可溶性环氧化物水解酶与肝肝环氧化物水解酶相同。J. Lipid Res. 2011. 52：712-719。
Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans-epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including inflammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purified from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i) purified mammalian sEH hydrolyses hepoxilin A(3) and B-3 with a V-max of 0.4-2.5 mu mol/mg/min; ii) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii) hepoxilin hydrolase activity was abolished in liver preparations from sEH(-/-) mice; and iv) liver homogenates of sEH(-/-) mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals.jlr We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrienoic acids. sEH inhibitors might have undesired side effects on hepoxilin signaling.-Cronin, A., M. Decker, and M. Arand. Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase. J. Lipid Res. 2011. 52: 712-719.