Hypothiocyanous acid is a more potent inducer of apoptosis and protein thiol depletion in murine macrophage cells than hypochlorous acid or hypobromous acid

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Mitchell M Lloyd, David M van Reyk, Michael Jonathan Davies, Clare Louise Hawkins

Hypohalous acids are generated by activated leucocytes, via the formation of H(2)O(2) and the release of peroxidase enzymes (myeloperoxidase and eosinophil peroxidase). These species are important bactericidal agents, but HOCl (hypochlorous acid) and HOBr (hypobromous acid) have also been implicated in tissue damage in a number of inflammatory diseases. HOSCN (hypothiocyanous acid; cyanosulfenic acid) is a milder, more thiol-specific, oxidant than HOCl or HOBr and as such may be a more potent inducer of cellular dysfunction due to selective targeting of critical thiol residues on proteins. In the present study, HOCl and HOBr are shown to react rapidly with macrophage (J774A.1) cells, resulting in a greater extent of cell lysis compared with HOSCN. However, HOSCN induces apoptosis and necrosis with greater efficacy, and at lower concentrations, than HOCl or HOBr. Apoptosis occurs in conjunction with an increased release of cytochrome c into the cytosol, but no associated increase in caspase activity. Similarly, apoptosis is observed on treating the cells in the presence of a caspase inhibitor, suggesting that it is mediated by a caspase-independent pathway. HOSCN oxidized protein thiols more efficiently than either HOCl or HOBr. The greater efficacy of HOSCN in inducing apoptosis is attributed to selective damage to critical mitochondrial membrane protein thiol groups, resulting in increased permeability and subsequent leakage of cytochrome c into the cytosol. This induction of damage by HOSCN may be of critical importance in people with elevated levels of SCN(-) (thiocyanate ions) arising from cigarette smoking, and plays a role in the pathologies associated with this biological insult.

Original languageEnglish
JournalBiochemical Journal
Volume414
Issue number2
Pages (from-to)271-80
Number of pages10
ISSN0264-6021
DOIs
Publication statusPublished - 1 Sep 2008
Externally publishedYes

    Research areas

  • Animals, Apoptosis, Bromates, Caspases, Cell Line, Cytochromes c, Glutathione, Glutathione Disulfide, Hypochlorous Acid, Macrophages, Mice, Necrosis, Oxidation-Reduction, Sulfhydryl Compounds, Thiocyanates

ID: 129670801