Comparative Oxidative Metabolism of Dietary Eicosapentaenoic Acid Hydroperoxide and Unoxidized Eicosapentaenoic Acid in Mice.

Eicosapentaenoic acid hydroperoxides (EPA-OOH) are oxidized derivatives of eicosapentaenoic acid formed during lipid peroxidation and metabolism; however, their physio-logical fate remains unclear. Here, we investigated the in vivo fate of dietary EPA-OOH. We synthesized stable isotope (13C)-labeled EPA-ethyl ester hydroperoxide (*EPA-EE-OOH) and its unoxidized counterpart (*EPA-EE) and administered them orally to mice. Exhaled air was collected at defined time points and analyzed by isotope-ratio mass spectrometry to determine the 13C/12C ratio of expired 13CO2. To evaluate gastric degradation, photo-oxidized EPA-EE-OOH was exposed to hydrochloric acid to simulate stomach conditions, and degradation products were characterized by gas chromatography-mass spectrometry and compared with those of unoxidized EPA-EE. Compared with *EPA-EE, *EPA-EE-OOH produced an earlier increase in expired 13CO2 (Δ13C peak 28.6 ‰ at 30 min) than *EPA-EE (Δ13C peak 27.4 ‰ at 240 min); however, cumulative 13CO2 excretion over 6 h did not differ significantly between treatments, indicating comparable overall catabolism. Under acidic conditions, EPA-EE-OOH underwent ac-id-catalyzed cleavage near the hydroperoxide moiety, yielding shorter-chain fatty acids and al-dehydes. These findings suggest that a fraction of dietary EPA-OOH is degraded in the gastroin-testinal tract into low-molecular-weight products that are rapidly catabolized, accounting for the early increase in expired 13CO2. To the best of our knowledge, our study is the first to report the in vivo catabolic behavior of dietary EPA-OOH. These findings provide new insight into its physiological significance.