Identification of novel F 2 -isoprostane metabolites by specific UDP-glucuronosyltransferases.

UDP-glucuronosyltransferases (UGTs) catalyze the conjugation of glucuronic acid with endogenous and exogenous lipophilic small molecules to facilitate their inactivation and excretion from the body. This represents approximately 35 % of all phase II metabolic transformations. Fatty acids and their oxidized eicosanoid derivatives can be metabolized by UGTs. F ₂ -isoprostanes (F ₂ -IsoPs) are eicosanoids formed from the free radical oxidation of arachidonic acid. These molecules are potent vasoconstrictors and are widely used as biomarkers of endogenous oxidative damage. An increasing body of evidence demonstrates the efficacy of measuring the β-oxidation metabolites of F ₂ -IsoPs rather than the unmetabolized F ₂ -IsoPs to quantify oxidative damage in certain settings. Yet, the metabolism of F ₂ -IsoPs is incompletely understood. This study sought to identify and characterize novel phase II metabolites of 15-F _2t -IsoP and 5-epi-5-F _2t -IsoP, two abundantly produced F ₂ -IsoPs, in human liver microsomes (HLM). Utilizing liquid chromatography-mass spectrometry, we demonstrated that glucuronide conjugates are the major metabolites of these F ₂ -IsoPs in HLM. Further, we showed that these molecules are metabolized by specific UGT isoforms. 15-F _2t -IsoP is metabolized by UGT1A3, 1A9, and 2B7, while 5-epi-5-F _2t -IsoP is metabolized by UGT1A7, 1A9, and 2B7. We identified, for the first time, the formation of intact glucuronide F ₂ -IsoPs in human urine and showed that F ₂ -IsoP glucuronidation is reduced in people supplemented with eicosapentaenoic and docosahexaenoic acids for 12 weeks. These studies demonstrate that endogenous F ₂ -IsoP levels can be modified by factors other than redox mechanisms.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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