Zhou Xue, Liu Ya-Nan, Yin Hou-Hua, Liu Jun-Yan
CNTTI of College of Pharmacy & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing, 400016, China; Department of Chemical Biology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
CNTTI of College of Pharmacy & Department of Anesthesia of the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China; Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, Chongqing, 400016, China; Department of Chemical Biology, College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
Biochem Biophys Res Commun. 2025 Sep 8;778:152394. doi: 10.1016/j.bbrc.2025.152394. Epub 2025 Jul 21.
Epoxyeicosatrienoic acids (EETs) have garnered extensive research interest as crucial signaling mediators that regulate key biological processes, including inflammation, pain and angiogenesis. While the metabolism of 8(9)-, 11(12)-, and 14(15)-EET has been well established to be metabolized in the presence of epoxide hydrolases, primarily soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH), the fate of 5(6)-EET was previously thought to be limited to its spontaneous chemical conversion into 5,6-dihydroxyeicosatrienoic acid (5,6-DHET) lactone. Here, we reported that the metabolism of 5(6)-EET is also enzymatically regulated by both sEH and mEH, occurring in parallel with its chemical formation to 5,6-DHET lactone. Specifically, in an epoxide hydrolases-free system, 5(6)-EET was rapidly converted to 5,6-DHET lactone, whereas 14(15)-EET remained relatively stable. In contrast, in a cellular system, EPHX2 (encodes sEH) knockout and EPHX1 (encodes mEH) knockout significantly attenuated 5(6)-EET degradation, indicating that both sEH and mEH actively mediate the metabolism of 5(6)-EET. Moreover, we observed that 5(6)-EET underwent conversion to 5,6-DHET lactone within the cellular environment as well. This study provides direct evidence that enzymatic metabolism of 5(6)-EET by epoxide hydrolases occurs concurrently with its spontaneous chemical transformation. This study expands our understanding of 5(6)-EET metabolism and reveals a previously unrecognized role of epoxide hydrolases in modulating relevant biological fate.
环氧二十碳三烯酸（EETs）作为调节包括炎症、疼痛和血管生成等关键生物学过程的重要信号介质，已引起广泛的研究兴趣。虽然8(9)-、11(12)-和14(15)-EET的代谢在环氧水解酶（主要是可溶性环氧水解酶（sEH）和微粒体环氧水解酶（mEH））存在的情况下已得到充分证实，但5(6)-EET的去向以前被认为仅限于其自发化学转化为5,6-二羟基二十碳三烯酸（5,6-DHET）内酯。在此，我们报道5(6)-EET的代谢也受到sEH和mEH的酶促调节，与其化学形成5,6-DHET内酯同时发生。具体而言，在无环氧水解酶的系统中，5(6)-EET迅速转化为5,6-DHET内酯，而14(15)-EET保持相对稳定。相反，在细胞系统中，EPHX2（编码sEH）基因敲除和EPHX1（编码mEH）基因敲除显著减弱了5(6)-EET的降解，表明sEH和mEH都积极介导5(6)-EET的代谢。此外，我们观察到5(6)-EET在细胞环境中也会转化为5,6-DHET内酯。这项研究提供了直接证据，证明环氧水解酶对5(6)-EET的酶促代谢与其自发化学转化同时发生。这项研究扩展了我们对5(6)-EET代谢的理解，并揭示了环氧水解酶在调节相关生物学命运方面以前未被认识的作用。
