Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant
Abstract
A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4′-hydroxy-3′methoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal–regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems.
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Apocynin is an antioxidant and scavenger of ROS like HOCl and hydrogen peroxide.
“Moreover, there are several factors that question the inhibitory effects of apocynin; notably, apocynin is an antioxidant and scavenger of ROS like HOCl and hydrogen peroxide (426, 735).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [426]
Apocynin directly scavenges ROS due to its antioxidant capacities.
“Instead, apocynin directly scavenges ROS due to its antioxidant capacities [340,395,396,397,398].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [396]
Apocynin was long considered as a specific Nox2 inhibitor, but several studies have shown that this is not the case.
“Apocynin was long considered as specific Nox2 inhibitor. However, several studies have shown that this is indeed not the case.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [396]
Apocynin may have antioxidant effects rather than being an NADPH oxidase inhibitor.
“Apocynin may have antioxidant effects rather than being an NADPH oxidase inhibitor [52].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [52]
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- Authors
- Heumüller, S., Wind, S., Barbosa-Sicard, E., Schmidt, H. H. H. W., Busse, R., Schröder, K., & Brandes, R. P.
- Affiliations
- From the Institut für Kardiovaskuläre Physiologie (S.H., E.B-S., R.B., K.S., R.P.B.), Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; Rudolf-Buchheim-Institut für Pharmakologie (S.W.), Justus-Liebig-Universität, Gießen, Germany; and the Department of Pharmacology and Centre for Vascular Health (H.H.H.W.S.), Monash-University, School of Biomedical Sciences, Victoria, Australia.
- Goethe University Frankfurt (DE)
- Venue
- Hypertension
- Published
- 2008-02
- Volume
- 51
- Issue
- 2
- Pages
- 211-217
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2096869450
- Cited by
- 735
- References
- 29
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 10 · 2023: 19 · 2022: 23 · 2021: 27 · 2020: 32 · 2019: 24 · 2018: 30 · 2017: 38 · 2016: 39 · 2015: 36 · 2014: 57 · 2013: 70 · 2012: 70
- FWCI
- 36.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- apocynin, NADPH oxidase, antioxidants, reactive oxygen species, superoxide, hydrogen peroxide, hydroxyl radicals, myeloperoxidase, NOX1, NOX2, NOX4, vascular smooth muscle cells, endothelial cells, p38 MAPK, Akt, ERK1/2, menadione, xanthine/xanthine oxidase
- MeSH terms
- Acetophenones, Antioxidants, Blood Vessels, Cell Line, Enzyme Activation, Enzyme Inhibitors, Humans, Isoenzymes, Leukocytes, Peroxidase, Peroxides, Superoxides, Transfection, Up-Regulation, Free Radical Scavengers, NADPH Oxidases
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