Identification and characterization of bioactive metabolites of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2.
J Biochem
; 173(4): 293-305, 2023 Mar 31.
Article
em En
| MEDLINE
| ID: mdl-36539331
ABSTRACT
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.
Palavras-chave
12-HHT.Abbreviations: 10,11dh-12-KHT, 10,11-dihydro-12-keto-heptadecatrienoic acid; 12-HHT, 12(S)-hydroxyheptadecatrienoic acid; 12-KHT, 12-keto-heptadecatrienoic acid; 13,14dh-15k-PGs, 13,14-dihydro-15-keto-prostaglandins; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; AA, arachidonic acid; BLT2, leukotriene B4 receptor 2; COX, cyclooxygenase; FA, formic acid; LT, leukotriene; PG, prostaglandin; PLA2, phospholipase A2; PTGR, prostaglandin reductase; TGF, transforming growth factor; Tx, thromboxane; TxAS, TxA synthase; 15-PGDH; BLT2; arachidonic acid; prostaglandins
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores do Leucotrieno B4
/
Ácidos Graxos Insaturados
Tipo de estudo:
Diagnostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Biochem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão