Abstract
Electrophilic nitro-fatty acids [NO2-FAs (fatty acid nitroalkenes)] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials. A detailed description of the pharmacokinetics (PK) of NO2-FAs is complicated by the capability of electrophilic fatty acids to alkylate thiols reversibly and become esterified in various complex lipids, and the instability of the nitroalkene moiety during enzymatic and base hydrolysis. Herein, we report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously detectable and prototypical NO2-FA, 10-nitro-oleic acid (10-NO2-OA), in dogs after oral administration. Supported by HPLC-high-resolution-MS/MS analysis of synthetic and plasma-derived 10-NO2-OA-containing triacylglycerides (TAGs), we show that a key mechanism of NO2-FA distribution is an initial esterification into complex lipids. Quantitative analysis of plasma free and esterified lipid fractions confirmed time-dependent preferential incorporation of 10-NO2-OA into TAGs when compared with its principal metabolite, 10-nitro-stearic acid. Finally, new isomers of 10-NO2-OA were identified in vivo, and their electrophilic reactivity and metabolism characterized. Overall, we reveal that NO2-FAs display unique PK, with the principal mechanism of tissue distribution involving complex lipid esterification, which serves to shield the electrophilic character of this mediator from plasma and hepatic inactivation and thus permits efficient distribution to target organs.
Highlights
Electrophilic nitro-fatty acids [NO2-FAs] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials
We reveal that the systemic distribution and targeted delivery of orally administered NO2-FA occur as complex lipid esterified species, following esterification and stabilization in triglycerides (TAGs)
Structural characterization of 10-NO2-OA-TAG The TAG esterification of NO2-FAs upon intestinal absorption could have a significant impact on NO2-FA metabolism and distribution
Summary
Electrophilic nitro-fatty acids [NO2-FAs (fatty acid nitroalkenes)] showed beneficial signaling actions in preclinical studies and safety in phase 1 clinical trials. We report the mechanism and kinetics of absorption, metabolism, and distribution of the endogenously detectable and prototypical NO2-FA, 10-nitro-oleic acid (10-NO2-OA), in dogs after oral administration. Supported by HPLC-high-resolution-MS/MS analysis of synthetic and plasma-derived 10-NO2-OA-containing triacylglycerides (TAGs), we show that a key mechanism of NO2-FA distribution is an initial esterification into complex lipids. As a covalently acting endogenous mediator and a class of new drug candidates, electrophilic nitro-fatty acids [NO2FAs (fatty acid nitroalkenes)] have displayed beneficial effects in preclinical animal models of metabolic and inflammatory disease [2,3,4,5,6,7]. NO2-FAs are generated during inflammation and digestion by reactions between unsaturated fatty acids and the Abbreviations: ADME, absorption, distribution, metabolism, and excretion; BME, -mercaptoethanol; Cmax, maximum concentration; CE, cholesterol ester; HR, high-resolution; MAG+DAG, monoglyceride+. NO2FAs have been shown to activate Nrf, PPAR , and heat shock factor-1-dependent gene expression, and inhibit NF-kB-dependent pro-inflammatory gene expression and directly inhibit enzymes, such as soluble epoxide hydrolase and xanthine oxidoreductase [17,18,19,20,21,22]
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