Superoxide-dependent oxidation of extracellular reducing agents by isolated neutrophils

Edwin Thomas, D. B. Learn, M. M. Jefferson, W. Weatherred

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Incubation of stimulated neutrophils with sulfhydryl (RSH) compounds or ascorbic acid (ascorbate) results in rapid superoxide (O(2̄))-dependent oxidation of these reducing agents. Oxidation of RSH compounds to disulfides (RSSR) is faster than the rate of O(2̄) production by the neutrophil NADPH-oxidase, whereas about one ascorbate is oxidized per O(2̄). Ascorbate is oxidized to dehydroascorbate, which is also oxidized but at a slower rate. Oxidation is accompanied by a large increase in oxygen (O2) uptake that is blocked by superoxide dismutase. Lactoferrin does not inhibit, indicating that ferric (Fe3+) ions are not required, and Fe3+-lactoferrin does not catalyze RSH or ascorbate oxidation. Two mechanisms contribute to oxidation: 1) O(2̄) oxidizes ascorbate or reduced glutathione and is reduced to hydrogen peroxide (H2O2), which also oxidizes the reductants. O(2̄) reacts directly with ascorbate, but reduced glutathione oxidation is mediated by the reaction of O(2̄) with manganese (Mn2+). The H2O2-dependent portion of oxidation is mediated by myeloperoxidase-catalyzed oxidation of chloride to hypochlorous acid (HOCl) and oxidation of the reductants by HOCl. 2) O(2̄) initiates Mn2+-dependent auto-oxidation reactions in which RSH compounds are oxidized and O2 is reduced. Part of this oxidation is due to the RSH-oxidase activity of myeloperoxidase. This activity is blocked by superoxide dismutase but does not require O(2̄) production by the NADPH-oxidase, indicating that myeloperoxidase produces O(2̄) when incubated with RSH compounds. It is proposed that an important role for O(2̄) in the cytotoxic activities of phagocytic leukocytes is to participate in oxidation of reducing agents in phagolysosomes and the extracellular medium. Elimination of these protective agents allows H2O2 and products of peroxidase/H2O2/halide systems to exert cytotoxic effects.

Original languageEnglish (US)
Pages (from-to)2178-2186
Number of pages9
JournalJournal of Biological Chemistry
Volume263
Issue number5
StatePublished - 1988
Externally publishedYes

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Reducing Agents
Superoxides
Peroxidase
Neutrophils
Hypochlorous Acid
Oxidation
Lactoferrin
NADPH Oxidase
Superoxide Dismutase
Glutathione
Protective Agents
Phagosomes
Manganese
Sulfhydryl Compounds
Disulfides
Hydrogen Peroxide
Ascorbic Acid
Chlorides
Oxidoreductases
Leukocytes

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Superoxide-dependent oxidation of extracellular reducing agents by isolated neutrophils. / Thomas, Edwin; Learn, D. B.; Jefferson, M. M.; Weatherred, W.

In: Journal of Biological Chemistry, Vol. 263, No. 5, 1988, p. 2178-2186.

Research output: Contribution to journalArticle

Thomas, E, Learn, DB, Jefferson, MM & Weatherred, W 1988, 'Superoxide-dependent oxidation of extracellular reducing agents by isolated neutrophils', Journal of Biological Chemistry, vol. 263, no. 5, pp. 2178-2186.
Thomas, Edwin ; Learn, D. B. ; Jefferson, M. M. ; Weatherred, W. / Superoxide-dependent oxidation of extracellular reducing agents by isolated neutrophils. In: Journal of Biological Chemistry. 1988 ; Vol. 263, No. 5. pp. 2178-2186.
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N2 - Incubation of stimulated neutrophils with sulfhydryl (RSH) compounds or ascorbic acid (ascorbate) results in rapid superoxide (O(2̄))-dependent oxidation of these reducing agents. Oxidation of RSH compounds to disulfides (RSSR) is faster than the rate of O(2̄) production by the neutrophil NADPH-oxidase, whereas about one ascorbate is oxidized per O(2̄). Ascorbate is oxidized to dehydroascorbate, which is also oxidized but at a slower rate. Oxidation is accompanied by a large increase in oxygen (O2) uptake that is blocked by superoxide dismutase. Lactoferrin does not inhibit, indicating that ferric (Fe3+) ions are not required, and Fe3+-lactoferrin does not catalyze RSH or ascorbate oxidation. Two mechanisms contribute to oxidation: 1) O(2̄) oxidizes ascorbate or reduced glutathione and is reduced to hydrogen peroxide (H2O2), which also oxidizes the reductants. O(2̄) reacts directly with ascorbate, but reduced glutathione oxidation is mediated by the reaction of O(2̄) with manganese (Mn2+). The H2O2-dependent portion of oxidation is mediated by myeloperoxidase-catalyzed oxidation of chloride to hypochlorous acid (HOCl) and oxidation of the reductants by HOCl. 2) O(2̄) initiates Mn2+-dependent auto-oxidation reactions in which RSH compounds are oxidized and O2 is reduced. Part of this oxidation is due to the RSH-oxidase activity of myeloperoxidase. This activity is blocked by superoxide dismutase but does not require O(2̄) production by the NADPH-oxidase, indicating that myeloperoxidase produces O(2̄) when incubated with RSH compounds. It is proposed that an important role for O(2̄) in the cytotoxic activities of phagocytic leukocytes is to participate in oxidation of reducing agents in phagolysosomes and the extracellular medium. Elimination of these protective agents allows H2O2 and products of peroxidase/H2O2/halide systems to exert cytotoxic effects.

AB - Incubation of stimulated neutrophils with sulfhydryl (RSH) compounds or ascorbic acid (ascorbate) results in rapid superoxide (O(2̄))-dependent oxidation of these reducing agents. Oxidation of RSH compounds to disulfides (RSSR) is faster than the rate of O(2̄) production by the neutrophil NADPH-oxidase, whereas about one ascorbate is oxidized per O(2̄). Ascorbate is oxidized to dehydroascorbate, which is also oxidized but at a slower rate. Oxidation is accompanied by a large increase in oxygen (O2) uptake that is blocked by superoxide dismutase. Lactoferrin does not inhibit, indicating that ferric (Fe3+) ions are not required, and Fe3+-lactoferrin does not catalyze RSH or ascorbate oxidation. Two mechanisms contribute to oxidation: 1) O(2̄) oxidizes ascorbate or reduced glutathione and is reduced to hydrogen peroxide (H2O2), which also oxidizes the reductants. O(2̄) reacts directly with ascorbate, but reduced glutathione oxidation is mediated by the reaction of O(2̄) with manganese (Mn2+). The H2O2-dependent portion of oxidation is mediated by myeloperoxidase-catalyzed oxidation of chloride to hypochlorous acid (HOCl) and oxidation of the reductants by HOCl. 2) O(2̄) initiates Mn2+-dependent auto-oxidation reactions in which RSH compounds are oxidized and O2 is reduced. Part of this oxidation is due to the RSH-oxidase activity of myeloperoxidase. This activity is blocked by superoxide dismutase but does not require O(2̄) production by the NADPH-oxidase, indicating that myeloperoxidase produces O(2̄) when incubated with RSH compounds. It is proposed that an important role for O(2̄) in the cytotoxic activities of phagocytic leukocytes is to participate in oxidation of reducing agents in phagolysosomes and the extracellular medium. Elimination of these protective agents allows H2O2 and products of peroxidase/H2O2/halide systems to exert cytotoxic effects.

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