Intracellular glutathione protects human monocyte-derived macrophages from hypochlorite damage

Yang, Ya-Ting; Whiteman, Matthew; Gieseg, Steven P.

doi:10.1016/j.lfs.2012.03.002

Cited by 23 publications

(15 citation statements)

References 47 publications

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“…The stoichiometry for HOCl scavenging by thiols is 1:2 is less than the >2:1 ratio for the reaction of HOCl and 5HT reported here. Glutathione is the major thiol-bearing scavenger of hypohalous acid in the body [45]. HOCl oxidizes the thiol moiety of this tripeptide to either a disulfide or a sulfonyl chloride [45, 46].…”

Section: Discussionmentioning

confidence: 99%

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Serotonin as a putative scavenger of hypohalous acid in the brain

Kalogiannis¹,

Delikatny²,

Jeitner³

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Neurodegenerative disorders represent the culmination of numerous insults including oxidative stress. The long etiology of most of these disorders suggests that lessening the effects of one of more of the insults could significantly delay disease onset. Antioxidants have been tested as possible therapeutics for neurodegenerative disorders, but with little success. Here we report that serotonin acts as a scavenger of hypochlorous acid (HOCl) in the brain. Serotonin was shown to prevent the oxidation of 2-thio-5-nitrobenzoate by HOCl in a biphasic manner. The first phase was a partial scavenging that occurred at concentrations of serotonin that exceeded those of HOCl. 1H-NMR studies indicated that HOCl chlorinates both the aryl and akyl nitrogen atoms of serotonin. Thus, the residual but lower oxidation of 2-thio-5-nitrobenzoate that occured during the first phase of scavenging is likely to due to formation of serotonergic chloramines. A second phase of scavenging occurred at concentrations of HOCl that exceeded those of serotonin. Under these conditions, the chlorinated serotonin polymerized and formed inert aggregates. Serotonin was further shown to prevent the loss of cells and cellular α-ketoglutarate dehydrogenase activity caused by HOCl. Extracellular concentrations of serotonin in the brain can be elevated with selective serotonin reuptake inhibitors and suggests that such compounds could be used to increase the cerebral antioxidant capacity. Acute administration of selective serotonin reuptake inhibitors to mice treated with endotoxin partially mitigated sickness behavior and protein chlorination in the brain. These observations suggest that serotonin may act to suppress chlorinative stress in the brain.

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Section: Discussionmentioning

confidence: 99%

“…Glutathione is the major thiol-bearing scavenger of hypohalous acid in the body [45]. HOCl oxidizes the thiol moiety of this tripeptide to either a disulfide or a sulfonyl chloride [45, 46]. The oxidation to the sulfonyl chloride, however, effectively destroys glutathione.…”

Section: Discussionmentioning

confidence: 99%

Serotonin as a putative scavenger of hypohalous acid in the brain

Kalogiannis¹,

Delikatny²,

Jeitner³

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…We have previously shown that 2 μmol/L of 7,8-dihydroneopterin inhibits LDL oxidation [13], although 50-100 μmol/L is required to prevent oxLDL-or HOCl-induced cell death [16][17][18]. It is possible that macrophage cell death occurs at a very localised cellular level, so concentrations of 7,8-dihydroneopterin around the cells may reach protective levels.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophage uptake of oxidised LDL (oxLDL) is decreased by 7,8-dihydroneopterin-mediated down-regulation of the CD36 scavenger receptor [16]. Macrophage necrosis by HOCl, oxLDL and peroxyl radicals is also inhibited by 7,8-dihydroneopterin [16][17][18][19]. HOCl reacts extremely rapidly with 7,8-dihydroneopterin to generate neopterin [20,21], suggesting that a significant amount of the neopterin measured in serum and urine may be from the scavenging of HOCl released by neutrophils and macrophages during inflammation.…”

Section: Introductionmentioning

confidence: 99%

Neopterin and 7,8-dihydroneopterin are generated within atherosclerotic plaques

et al. 2015

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AbstractPlasma neopterin correlates with the level of cardiovascular disease. Neopterin is the oxidation product of 7,8-dihydroneopterin, which is released by γ-interferon-stimulated macrophages. 7,8-Dihydroneopterin is a potent antioxidant, which inhibits lipid oxidation, macrophage cell death and scavenger receptor CD36 expression. The concentration of neopterin within atherosclerotic plaques was measured in tissue removed from carotid and femoral arteries. The excised plaques were cut into 3-mm-thick sections, and each section was analysed for neopterin, total neopterin, cholesterol, lipid peroxides, α-tocopherol and protein-bound 3,4-dihydroxyphenylalanine. Selected plaques were placed in tissue culture, and the media was analysed for 7,8-dihydroneopterin and neopterin release. Total neopterin levels ranged from 14 to 18.8 nmol/g of tissue. Large ranges of values were seen both within the same plaque and between plaques. No correlation between neopterin and any of the other analytes was observed, nor was there any significant trend in levels along the length of the plaques. γ-Interferon stimulation of cultured plaque generated total neopterin concentrations from 1 to 4 nmol/(g 24 h). The level of 7,8-dihydroneopterin generated within the plaque was within the range that inhibits lipid oxidation. The data show that atherosclerotic plaques are extremely dynamic in biochemistry and are the likely source of the plasma 7,8-dihydroneopterin and neopterin.

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“…Detailed mechanistic insight into how exogenously added or self-generated HOCl mediates the MPO heme moiety has recently been elucidated [32,34]. Therefore, factors that influence rates of HOCl removal are of growing interest [20,[35][36][37][38][39][40]. Here, we examine the ability of MLT to prevent HOCl-mediated heme destruction and subsequent iron release.…”

Section: Introductionmentioning

confidence: 99%