Oxidative fragmentation of hydroxy octadecadienoates generates biologically active gamma-hydroxyalkenals.

Oxidative fragmentation of polyunsaturated fatty acids (PUFAs) in vivo generates cytotoxic aldehydes. Among these, 4-hydroxynon-2-enal and analogous gamma-hydroxyalkenal phosphatidylcholines (PCs) have attracted attention because these oxidatively truncated lipids are biologically active and have been implicated in diseases. A previous study showed that hydroxydienes, generated by allylic oxygenation of linoleic acid, are unreactive toward oxidative fragmentation. We now show that, in the presence of hydroperoxides, hydroxydienes fragment as readily as the corresponding hydroperoxydienes, generating gamma-hydroxyalkenals. In a physiomimetic model study, myeloperoxidase-promoted free radical-induced fragmentation of either hydroperoxy- or hydroxyoctecadienoate esters of 2-lyso-PC in small unilamellar vesicles produced the 9-hydroxy-12-oxododec-10-enoic acid (HODA) ester HODA-PC. Therefore, hydroxydienes, that are generally more abundant in vivo than hydroperoxydienes, are plausible intermediates in the production of oxidatively truncated lipids in vivo where a constant flux of radicals and hydroperoxides is present. Our findings also show that the formation of dioxetane intermediates through peroxyradical cyclization is not required to achieve oxidative fragmentation of PUFAs.