4.7 Article

Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde

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ANTIOXIDANTS
卷 12, 期 2, 页码 -

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MDPI
DOI: 10.3390/antiox12020504

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myeloperoxidase; chlorinated lipids; N-acetyl cysteine; neutrophils

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Hypochlorous acid is formed when leukocyte myeloperoxidase attacks the phospholipid plasmalogen molecular subclass, leading to the formation of 2-chlorofatty aldehydes (2-ClFALDs). The biological role of 2-ClFALD is not well understood. In this study, the effects of 2-ClHDA, an analog of 2-ClFALD, on the metabolic activity of RAW 264.7 cells were investigated. It was found that 2-ClHDA reduced the metabolic activity of the cells in a dose-dependent manner. Furthermore, N-acetyl cysteine (NAC) was shown to reduce the toxic effects of 2-ClFALD by reducing protein modification.
Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl- (HDA-NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA-NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification.

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