Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 24, Issue 1, Pages 111-118Publisher
AMER CHEMICAL SOC
DOI: 10.1021/tx100305b
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Funding
- NIH [EY016813, GM21249, HL053315]
- NATIONAL EYE INSTITUTE [R01EY016813] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL053315] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM021249] Funding Source: NIH RePORTER
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Elevated levels of lysophosphatidylcholine (lysoPC), present in oxidatively damaged low-density lipoprotein (oxLDL), are implicated in cardiovascular complications. LysoPC is generated by Free radical-catalyzed oxidation of polyunsaturated PCs to oxidatively truncated phosphophatidylcholines (oxPCs). It is known that oxPCs are especially susceptible to hydrolysis by platelet-activating factor acetylhydrolase, a phospholipase (PL) A(2) that exists in plasma largely in association with LDL. Drugs that aim to prevent the generation of lysoPC by inhibiting this PLA(2)-catalyzed hydrolysis are in advanced clinical trials. We now report that spontaneous deacylation oxPCs, such as 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphocholine, occurs readily under physiological conditions of temperature and pH (t(1/2) = 30 min at 37 degrees C and pH 7.4). We also show that this reaction proceeds through an intramolecular transesterification mechanism. Because antiphospholipase drugs cannot block this nonenzymatic pathway to lysoPC, additional therapeutic measures may be needed to avoid the pathological consequences of the newly discovered biomolecular chemistry of oxPCs.
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