An O-1(2) Route to gamma-Hydroxyalkenal Phospholipids by Vitamin E-Induced Fragmentation of Hydroperoxydiene-Derived Endoperoxides

作者:Gu Xiaodong; Zhang Wujuan; Choi Jaewoo; Li Wei; Chen Xi; Laird James M; Salomon Robert G*
来源:Chemical Research in Toxicology, 2011, 24(7): 1080-1093.
DOI:10.1021/tx200093m

摘要

Biologically active phospholipids that incorporate an oxidatively truncated acyl chain terminated by a gamma-hydroxyalkenal are generated in vivo. The gamma-hydroxyalkenal moiety protrudes from lipid bilayers like whiskers that serve as ligands for the scavenger receptor CD36, fostering endocytosis, e.g., of oxidatively damaged photoreceptor cell outer segments by retinal pigmented endothelial cells. They also covalently modify proteins generating carboxyalkyl pyrroles incorporating the E-amino group of protein lysyl residues. We postulated that gamma-hydroxyalkenals could be generated, e.g., in the eye, through fragmentation of hydroperoxy endoperoxides produced in the retina through reactions of singlet molecular oxygen with polyunsaturated phospholipids. Since phospholipid esters are far more abundant in the retina than free fatty acids, we examined the influence of a membrane environment on the fate of hydroperoxy endoperoxides. We now report that linoleate hydroperoxy endoperoxides in thin films and their phospholipid esters in biomimetic membranes fragment to gamma-hydroxyalkenals, and fragmentation is stoichiometrically induced by vitamin E. The product distribution from fragmentation of the free acid in the homogeneous environment of a thin film is remarkably different from that from the corresponding phospholipid in a membrane. In the membrane, further oxidation of the initially formed gamma-hydroxyalkenal to a butenolide is disfavored. A conformational preference for the gamma-hydroxyalkenal, to protrude from the membrane into the aqueous phase, may protect it from oxidation induced by lipid hydroperoxides that remain buried in the lipophilic membrane core.

  • 出版日期2011-7