Cytotoxicity of phosphatidylcholine hydroperoxides is exerted through decomposition of fatty acid hydroperoxide moiety

The cytotoxicity of phosphatidylcholine hydroperoxides synthesized regioselectively and stereoselectively was examined in human umbilical vein endothelial cells. Phosphatidylcholine hydroperoxides were readily incorporated into cells, after which the contents declined gradually. Phosphatidylcholine with an arachidonic acid hydroperoxide residue was toxic to cells, while phosphatidylcholine with a linoleic acid hydroperoxide residue had no effect. The toxicity of phosphatidylcholine with arachidonic acid hydroperoxide disappeared after the reduction of the hydroperoxide by triphenylphosphine. Phosphatidylcholine with arachidonic acid hydroperoxide that had decomposed partially upon standing at room temperature was much more toxic than the pure hydroperoxide. 4-Hydroxynonenal, known widely as a toxic secondary product in the lipid peroxidation of polyunsaturated fatty acids, was detected in the decomposition mixture of phosphatidylcholine hydroperoxide. Phosphatidylcholine hydroperoxide incorporated into cells did not show toxicity when the hydroperoxide-containing medium was changed to growth medium after a short time. On the other hand, the phosphatidylcholine hydroperoxide was toxic in cells treated with the lipophilic free radical generator, 2,2'-azobis(2,4-dimethylvaleronitrile). In addition, cells were damaged by long-term treatment in medium containing phosphatidylcholine hydroperoxide and its decomposition products. These results suggest that the toxicity of phosphatidylcholine hydroperoxides is exerted by toxic compounds arising from the decomposition of the hydroperoxide moiety.