Abstract
α-Chlorofatty aldehydes (α-ClFALDs) and α-bromofatty aldehydes (α-BrFALDs) are produced in activated neutrophils and eosinophils. This study investigated the ability of α-BrFALD and α-ClFALD to react with the thiols of GSH and protein cysteinyl residues. Initial studies showed that 2-bromohexadecanal (2-BrHDA) and 2-chlorohexadecanal (2-ClHDA) react with GSH producing the same fatty aldehyde-GSH adduct (FALD-GSH). In both synthetic and cellular reactions, FALD-GSH production was more robust with 2-BrHDA compared with 2-ClHDA as precursor. NaBr-supplemented phorbol myristate acetate (PMA)-activated neutrophils formed more α-BrFALD and FALD-GSH compared with non-NaBr-supplemented neutrophils. Primary human eosinophils, which preferentially produce hypobromous acid and α-BrFALD, accumulated FALD-GSH following PMA stimulation. Mice exposed to Br2 gas had increased levels of both α-BrFALD and FALD-GSH in the lungs, as well as elevated systemic plasma levels of FALD-GSH in comparison to mice exposed to air. Similar relative reactivity of α-ClFALD and α-BrFALD with protein thiols was shown using click analogs of these aldehydes. Collectively, these data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on α-BrFALD compared with α-ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.
Highlights
Abstract -Chlorofatty aldehydes ( --chlorofatty aldehyde (ClFALD)) and bromofatty aldehydes ( --bromofatty aldehyde (BrFALD)) are produced in activated neutrophils and eosinophils
-Halofatty aldehydes are produced by hypohalous acid attack of the vinyl ether bond of plasmalogen [1, 2]
-ClFALD was found in the lungs of mice and rats exposed to chlorine gas (Cl2) along with its GSH adduct [fatty aldehyde-GSH adduct (FALD-GSH)], and it was found to contribute to Abbreviations: -BrFALD, -bromofatty aldehyde; -ClFALD, -chlorofatty aldehyde; 2-BrHA, 2-bromohexadecanoic acid; 2-BrHDA, 2-bromohexadecanal; 2-BrHDyA, 2-bromohexadec-15-ynal; 2-ClHA, 2-chlorohexadecanoic acid; 2-ClHDA, 2-chlorohexadecanal; 2-ClHDyA, 2-chlorohexadec-15-ynal; 2-ClHOH, 2-chlorohexadecanol; FALD-GSH, fatty aldehyde-GSH adduct; HDA, hexadecanal; HDA-GSH, 2-halohexadecanal adduct with GSH; HDyA, hexadec-15-ynal; HOBr, hypobromous acid; HOCl, hypochlorous acid; MPO, myeloperoxidase; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; NAC, N-acetylcysteine; NEM, N-ethylmaleimide; ODA-GSH, 2-halooctadecanal adduct with GSH; PMA, phorbol myristate acetate
Summary
Abstract -Chlorofatty aldehydes ( -ClFALDs) and bromofatty aldehydes ( -BrFALDs) are produced in activated neutrophils and eosinophils. Similar relative reactivity of -ClFALD and -BrFALD with protein thiols was shown using click analogs of these aldehydes These data demonstrate that GSH and protein adduct formation are much greater as a result of nucleophilic attack of cysteinyl residues on -BrFALD compared with -ClFALD, which was observed in both primary leukocytes and in mice exposed to bromine gas.—Duerr, M. -ClFALD was found in the lungs of mice and rats exposed to chlorine gas (Cl2) along with its GSH adduct [fatty aldehyde-GSH adduct (FALD-GSH)], and it was found to contribute to Abbreviations: -BrFALD, -bromofatty aldehyde; -ClFALD, -chlorofatty aldehyde; 2-BrHA, 2-bromohexadecanoic acid; 2-BrHDA, 2-bromohexadecanal; 2-BrHDyA, 2-bromohexadec-15-ynal; 2-ClHA, 2-chlorohexadecanoic acid; 2-ClHDA, 2-chlorohexadecanal; 2-ClHDyA, 2-chlorohexadec-15-ynal; 2-ClHOH, 2-chlorohexadecanol; FALD-GSH, fatty aldehyde-GSH adduct; HDA, hexadecanal; HDA-GSH, 2-halohexadecanal adduct with GSH; HDyA, hexadec-15-ynal; HOBr, hypobromous acid; HOCl, hypochlorous acid; MPO, myeloperoxidase; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; NAC, N-acetylcysteine; NEM, N-ethylmaleimide; ODA-GSH, 2-halooctadecanal adduct with GSH; PMA, phorbol myristate acetate. Because bromine is a better leaving group in nucleophilic substitution reactions, it follows that BrFALD will be very reactive with GSH
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