Inhibition of plasma lipid oxidation induced by peroxyl radicals, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen by clinical drugs

doi:10.1016/j.bmcl.2016.10.033

Bioorganic & Medicinal Chemistry Letters

Volume 26, Issue 22, 15 November 2016, Pages 5411-5417

https://doi.org/10.1016/j.bmcl.2016.10.033 Get rights and content

Highlights

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Plasma oxidation by five kinds of biological oxidants produced lipid hydroperoxides.
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Antioxidant effects of six clinical drugs were determined by nature of oxidants.
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Probucol and edaravone suppressed plasma oxidation by peroxynitrite and hypochlorite.
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Troglitazone and edaravone inhibited 15-lipoxygenase mediated plasma lipid oxidation.
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Multiple antioxidants with different specificity and reactivity are required in vivo.

Abstract

With increasing evidence showing the involvement of oxidative stress in the pathogenesis of various diseases, the effects of clinical drugs possessing antioxidant functions have received much attention. The unregulated oxidative modification of biological molecules leading to diseases is mediated by multiple oxidants including free radicals, peroxynitrite, hypochlorite, lipoxygenase, and singlet oxygen. The capacity of antioxidants to scavenge or quench oxidants depends on the nature of oxidants. In the present study, the antioxidant effects of several clinical drugs against plasma lipid oxidation induced by the aforementioned five kinds of oxidants were investigated from the production of lipid hydroperoxides, which have been implicated in the pathogenesis of various diseases. Troglitazone acted as a potent peroxyl radical scavenger, whereas probucol and edaravone showed only moderate reactivity and carvedilol, pentoxifylline, and ebselen did not act as radical scavenger. Probucol and edaravone suppressed plasma oxidation mediated by peroxynitrite and hypochlorite. Troglitazone and edaravone inhibited 15-lipoxygenase mediated plasma lipid oxidation, the IC₅₀ being 20 and 34 μM respectively. None of the drugs used in this study suppressed plasma lipid oxidation by singlet oxygen. This study shows that the antioxidant effects of drugs depend on the nature of oxidants and that antioxidants against multiple oxidants are required to cope with oxidative stress in vivo.

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Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References and notes (61)

E. Niki
Free Radic. Biol. Med.
(2014)
M. Vardi et al.
J. Lipid Res.
(2013)
N. Noguchi et al.
Biochem. Pharmacol.
(2000)
K. Oettl et al.
Biochem. Pharmacol.
(2001)
K. Prasad et al.
Atherosclerosis
(2007)
J.C. Parker
Adv. Drug Deliv. Rev.
(2002)
N. Noguchi et al.
Atherosclerosis
(1996)
M.J. Parnham et al.
Biochem. Pharmacol.
(2013)
N. Noguchi et al.
Biochem. Pharmacol.
(1992)
E. Niki
Arch. Biochem. Biophys.
(2016)

E. Niki

Free Radic. Biol. Med.

(2010)

E. Niki

Free Radic. Biol. Med.

(2009)

S. Carballal et al.

Biochim. Biophys. Acta.

(2014)

R. Zhang et al.

J. Biol. Chem.

(2002)

G. Aldini et al.

Redox Biol.

(2015)

E. Niki

Biochim. Biophys. Acta.

(2014)

M. Morita et al.

Redox Biol.

(2016)

M. Takashima et al.

Free Radic. Biol. Med.

(2012)

P. Torres et al.

Bioorg. Med. Chem.

(2008)

N. Itoh et al.

Bioorg. Med. Chem. Lett.

(2007)

J. Belkner et al.

J. Biol. Chem.

(1998)

H. Yamashita et al.

FEBS Lett.

(1999)

A.W. Girotti

J. Lipid Res.

(1998)

P. Di Mascio et al.

Am. J. Clin. Nutr.

(1991)

P.K. Witting et al.

J. Biol. Chem.

(2005)

E. Kamogawa et al.

Bioorg. Med. Chem. Lett.

(2014)

C.X. Santos et al.

Arch. Biochem. Biophys.

(1999)

N. Noguchi et al.

Arch. Biochem. Biophys.

(2002)

E. Niki et al.

Am. J. Clin. Nutr.

(1995)

B.M. Best et al.

Curr. Ther. Res. Clin. Exp.

(2003)

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Inhibition of plasma lipid oxidation induced by peroxyl radicals, peroxynitrite, hypochlorite, 15-lipoxygenase, and singlet oxygen by clinical drugs

Highlights

Abstract

Graphical abstract

Section snippets

Acknowledgements

Free Radic. Biol. Med.

J. Lipid Res.

Biochem. Pharmacol.

Biochem. Pharmacol.

Atherosclerosis

Adv. Drug Deliv. Rev.

Atherosclerosis

Biochem. Pharmacol.

Biochem. Pharmacol.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Biochim. Biophys. Acta.

J. Biol. Chem.

Redox Biol.

Biochim. Biophys. Acta.

Redox Biol.

Free Radic. Biol. Med.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

FEBS Lett.

J. Lipid Res.

Am. J. Clin. Nutr.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Am. J. Clin. Nutr.

Curr. Ther. Res. Clin. Exp.