Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone

Paula M. Bozeman, Douglas B. Learn, Edwin Thomas

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Dapsone (4,4′-diaminodiphenylsulfone) is an antimicrobial substance that also has anti-inflammatory activity, which has been attributed to inhibition of the leukocyte enzyme myeloperoxidase (MPO). We observed that dapsone was a much better inhibitor of the eosinophil peroxidase (EPO) in an assay that measured peroxidase-catalyzed oxidation of tetramethylbenzidine at pH 5.4. To clarify the specificity and pH-dependence of dapsone inhibition of the purified enzymes under more physiologic conditions, we studied peroxidase-catalyzed oxidation of chloride to the antimicrobial and cytotoxic agent hypochlorous acid. Taurine was added as a trap for hypochlorous acid, to prevent inactivation of the enzymes or chlorination of dapsone by hypochlorous acid. Dapsone was much more effective as an inhibitor of both MPO and EPO when chloride rather than tetramethylbenzidine was the substrate. Inhibition of both enzymes was greater at neutral pH than at acid pH (pH7 vs pH5), but EPO was more sensitive to inhibition than MPO regardless of pH. Inhibition was increased by lowering chloride, raising hydrogen peroxide, or lowering the enzyme concentration. Inhibition was accompanied by irreversible loss of enzyme activity, which was correlated with loss of the heme absorption spectrum, indicating chemical modification of the enzyme active site. EPO, but not MPO, was partially protected against inactivation by adding physiologic levels of bromide along with chloride. The results suggest that dapsone could prevent MPO- and EPO-mediated tissue injury at sites where the peroxidase enzymes are secreted and diluted into the neutral pH environment of the tissue interstitial space. Dapsone might not inhibit peroxidase-mediated antimicrobial activity, which occurs at high enzyme concentrations in the acid environment of phagolysosomes.

Original languageEnglish (US)
Pages (from-to)553-563
Number of pages11
JournalBiochemical Pharmacology
Volume44
Issue number3
DOIs
StatePublished - Aug 4 1992

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Eosinophil Peroxidase
Dapsone
Peroxidase
Leukocytes
Enzymes
Hypochlorous Acid
Chlorides
Tissue
Enzyme inhibition
Phagosomes
Oxidation
Acids
Chlorination
Halogenation
Taurine
Cytotoxins
Chemical modification
Enzyme activity
Anti-Infective Agents
Bromides

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone. / Bozeman, Paula M.; Learn, Douglas B.; Thomas, Edwin.

In: Biochemical Pharmacology, Vol. 44, No. 3, 04.08.1992, p. 553-563.

Research output: Contribution to journalArticle

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