Abstract
Nitrated fatty acids are endogenously present in human and animal tissues, as well as in plant-derived oils. In particular, 10-nitro oleic acid (10-NO2-OA) potently induces Nrf2-dependent antioxidant gene expression and inhibits TLR4/NF-κB signaling, thus promoting an overall cyto-protective and anti-inflammatory response. 10-NO2-OA has been extensively tested in animal models and is currently undergoing clinical evaluation in humans. Bio-elimination pathways for 10-NO2-OA were evaluated in rats (30 mg/kg·day) and in humans (0.34 mg/kg) using samples obtained from a double-blind, dose-rising clinical trial. Quantitative radiochromatographic/MS analysis indicated that the renal and fecal pathways are the main routes for 10-NO2-OA excretion in rats, and allowed the identification of 4-nitro-octanedioic acid (NO2-8:0-diCOOH) as the most abundant metabolite in rat urine. In addition, high resolution LC-MS/MS analysis revealed the presence of a novel series of urinary metabolites including ω-carboxylation and β-oxidation products, as well as N-acetylcysteine, taurine and sulfo-conjugates in both rats and humans. Overall, the findings reported herein not only provide valuable tools for the experimental evaluation of 10-NO2-OA levels in vivo, but importantly they also set the basis for monitoring its metabolism during potential clinical interventions in humans.
Highlights
Nitrated fatty acids are formed during digestion and inflammatory processes from the reaction between nitrogen dioxide (NO2) and mono and polyunsaturated fatty acids in both humans and animal models[1,2,3,4]
2% was excreted through exhaled air, 4.5% remained in the carcasses and 2% was retrieved from the cage washes
D1, D2 and D3 were identified in rat and human urine corresponding to N-acetylcysteine conjugates of 10-NO2-OA, A1 and A2, with the thioether bond located at carbons 9, 7 and 5, respectively (Fig. 4a,b)
Summary
Nitrated fatty acids are formed during digestion and inflammatory processes from the reaction between nitrogen dioxide (NO2) and mono and polyunsaturated fatty acids in both humans and animal models[1,2,3,4]. The chromatographic peak obtained for the metabolite A2 in human urine presented an additional peak at 13.81 min (18% of total A-2) with identical molecular composition and neutral loss of 47 amu (HNO2) that was not further characterized (Fig. 1b). C1 (NO2-16:0-diCOOH) and C2 (NO2-14:0-diCOOH) were only observed in human urine, displayed RT of 10.1 and 9.6 min respectively, and generated both the [HNO2] and the NO2− characteristic losses upon collision-induced fragmentation Fig. 2d–f does not show C1 and C2 but C3-C4-C5.
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