Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

Tracey B. Kajer, Kathryn E. Fairfull-Smith, Toshihide Yamasaki, Ken Ichi Yamada, Shanlin Fu, Steven E. Bottle, Clare L. Hawkins, Michael J. Davies

研究成果: ジャーナルへの寄稿記事

22 引用 (Scopus)

抄録

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, -OCl) generated by the myeloperoxidase (MPO)-H2O 2-Cl- system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79-86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 μM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl- substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89-99% decreased rate of reduction) and activated human neutrophils (62-75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

元の言語英語
ページ(範囲)96-105
ページ数10
ジャーナルFree Radical Biology and Medicine
70
DOI
出版物ステータス出版済み - 5 2014

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Oxidants
Peroxidase
Neutrophils
Inhibitory Concentration 50
Plasma (human)
Rigid structures
Hypochlorous Acid
Reducing Agents
Scavenging
Superoxides
Superoxide Dismutase
Anions
Toxicity
Animals
Leukocytes
Substitution reactions
Animal Models
Antioxidants
Plasmas
Oxidation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

これを引用

Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides. / Kajer, Tracey B.; Fairfull-Smith, Kathryn E.; Yamasaki, Toshihide; Yamada, Ken Ichi; Fu, Shanlin; Bottle, Steven E.; Hawkins, Clare L.; Davies, Michael J.

:: Free Radical Biology and Medicine, 巻 70, 05.2014, p. 96-105.

研究成果: ジャーナルへの寄稿記事

Kajer, Tracey B. ; Fairfull-Smith, Kathryn E. ; Yamasaki, Toshihide ; Yamada, Ken Ichi ; Fu, Shanlin ; Bottle, Steven E. ; Hawkins, Clare L. ; Davies, Michael J. / Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides. :: Free Radical Biology and Medicine. 2014 ; 巻 70. pp. 96-105.
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abstract = "The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, -OCl) generated by the myeloperoxidase (MPO)-H2O 2-Cl- system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79-86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 μM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl- substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89-99{\%} decreased rate of reduction) and activated human neutrophils (62-75{\%} decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.",
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T1 - Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

AU - Kajer, Tracey B.

AU - Fairfull-Smith, Kathryn E.

AU - Yamasaki, Toshihide

AU - Yamada, Ken Ichi

AU - Fu, Shanlin

AU - Bottle, Steven E.

AU - Hawkins, Clare L.

AU - Davies, Michael J.

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