Free radical oxidation of polyunsaturated fatty acids (PUFAs) and sterols (lipid peroxidation) are implicated in common human diseases such as atherosclerosis, asthma, Alzheimer's disease, Parkinson's disease, etc.. The bis-allylic methylene groups in PUFAs are susceptible to hydrogen atom abstraction, and we found that the reactivities of PUFAs are proportional to the number of bis-allylic methylene centers with docosahexaenoic acid (22:6, ?-3) being the most reactive one. The mechanism of free radical-mediated oxidation of PUFAs proceeds via a combination of oxygen addition, hydrogen atom transfer, �-fragmentation, peroxyl radical addition, intramolecular radical substitution on peroxide (SHi), and peroxyl radical cyclization. Recently, we found that 7-dehydrocholesterol (7-DHC), the immediate biosynthetic precursor to cholesterol, is the most reactive lipid molecule known to date toward free radical oxidation, giving rise to a number of biologically active oxysterols. The propagation rate constant for peroxidation of 7-DHC is 2260 M-1s-1, more than 200 times that of cholesterol (11 M-1s-1). From product studies, we found that peroxidation of 7-DHC was initiated by abstraction of H-9 or H-14 in the molecule, giving two pentadienyl radical intermediates, which was followed by well-precedented transformations observed in peroxidation reactions of PUFAs. When the peroxidation of 7-DHC was carried out in the presence of antioxidant vitamin-E, kinetic products that were derived from the bis-allylic peroxyl radical intermediates were observed and the levels of thermodynamic products were greatly reduced. This observation supports the oxidation mechanism that involves competition between hydrogen atom transfer, �-fragmentation, SHi, and 5-exo cyclization. The mechanistic studies on peroxidation of 7-DHC may provide a new aspect of view on diseases that are characterized by elevated levels of 7-DHC and on the consumption of vegetables (such as fungi) that are rich in ergosterol, an analogue of 7-DHC.

Mechanism of free radical peroxidation of polyunsaturated fatty acids and sterols

246th National Meeting (2013)

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