Yasukawa Ken, Okuno Toshiaki, Ogawa Narihito, Kobayashi Yuichi, Yokomizo Takehiko
Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
Drug Discovery Research Department, Sato Pharmaceutical Co., Ltd., Tokyo 140-0011, Japan.
J Biochem. 2023 Mar 31;173(4):293-305. doi: 10.1093/jb/mvac105.
12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity.
12(S)-羟基十七碳三烯酸（12-HHT）是一种通过环氧化酶途径由花生四烯酸合成的生物活性脂肪酸，作为低亲和力白三烯B4受体2（BLT2）的内源性配体。尽管12-HHT/BLT2轴有助于维持上皮稳态，但生理条件下12-HHT的代谢尚不清楚。在本研究中，在人巨核细胞系MEG01中检测到12-酮基十七碳三烯酸（12-KHT）和10,11-二氢-12-KHT（10,11dh-12-KHT）作为12-HHT的代谢产物。我们发现12-KHT和10,11dh-12-KHT分别由前列腺素降解的关键酶15-羟基前列腺素脱氢酶（15-PGDH）和前列腺素还原酶1（PTGR1）从12-HHT产生。15-PGDH抑制剂SW033291完全抑制了MEG01细胞中12-KHT和10,11dh-12-KHT的产生，导致12-HHT积累了9倍。12-KHT和10,11dh-12-KHT在小鼠皮肤伤口中产生，其水平被SW033291显著抑制。令人惊讶的是，12-KHT和10,11dh-12-KHT对BLT2的激动活性与12-HHT相当。综上所述，12-HHT先被15-PGDH代谢为12-KHT，然后被PTGR1代谢为10,11dh-12-KHT，且不丧失激动活性。
