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 |
| 巻 | 70 |
| DOI | |
| 出版物ステータス | 出版済み - 5 2014 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Physiology (medical)
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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
}
TY - JOUR
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.
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84896503124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896503124&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2014.02.011
DO - 10.1016/j.freeradbiomed.2014.02.011
M3 - Article
C2 - 24566469
AN - SCOPUS:84896503124
VL - 70
SP - 96
EP - 105
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
ER -