title: Evaluation of 10-Nitro Oleic Acid Bio-Elimination in Rats and Humans.
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.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Sonia R
authors.initials: SR
authors.lastname: Salvatore
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Dario A
authors.initials: DA
authors.lastname: Vitturi
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.|Fondazione Ri.MED, Palermo, 90133, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fazzari
authors.affiliation: Complexa Inc., Pittsburgh, PA, 15203, USA.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Jorkasky
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
mesh_terms: D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D066237:Intestinal Elimination; D008297:Male; D008875:Middle Aged; D009829:Oleic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination
chemical_list: C521487:10-nitro-oleic acid; D000975:Antioxidants; D009829:Oleic Acids