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Comparative pharmacology of chemically distinct NADPH oxidase inhibitors
Open accessAbstract
BACKGROUND AND PURPOSE Oxidative stress [i.e. increased levels of reactive oxygen species (ROS)] has been suggested as a pathomechanism of different diseases, although the disease‐relevant sources of ROS remain to be identified. One of these sources may be NADPH oxidases. However, due to increasing concerns about the specificity of the compounds commonly used as NADPH oxidase inhibitors, data obtained with these compounds may have to be re‐interpreted. EXPERIMENTAL APPROACH We compared the pharmacological profiles of the commonly used NADPH oxidase inhibitors, diphenylene iodonium (DPI), apocynin and 4‐(2‐amino‐ethyl)‐benzolsulphonyl‐fluoride (AEBSF), as well as the novel triazolo pyrimidine VAS3947. We used several assays for detecting cellular and tissue ROS, as none of them is specific and artefact free. KEY RESULTS DPI abolished NADPH oxidase‐mediated ROS formation, but also inhibited other flavo‐enzymes such as NO synthase (NOS) and xanthine oxidase (XOD). Apocynin interfered with ROS detection and varied considerably in efficacy and potency, as did AEBSF. Conversely, the novel NADPH oxidase inhibitor, VAS3947, consistently inhibited NADPH oxidase activity in low micromolar concentrations, and interfered neither with ROS detection nor with XOD or eNOS activities. VAS3947 attenuated ROS formation in aortas of spontaneously hypertensive rats (SHRs), where NOS or XOD inhibitors were without effect. CONCLUSIONS AND IMPLICATIONS Our data suggest that triazolo pyrimidines such as VAS3947 are specific NADPH oxidase inhibitors, while DPI and apocynin can no longer be recommended. Based on the effects of VAS3947, NADPH oxidases appear to be a major source of ROS in aortas of SHRs.
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“This includes Nox enzymes but also, for example, complex I of the ETC [63,250,251], iNOS [400,401] and XO [394,399] as well as calcium transporters [402].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [394]
In the citing paper
“However, due to its chemistry, it unselectively inhibits all flavin-containing enzymes of the cell [393,394,399].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [394]
In the citing paper
“VAS2870 was the first published inhibitor that resulted from a systematic screening effort for selective NADPH oxidase inhibitors by Tegtmeier and colleagues [394].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [394]
In the citing paper
“Thus, ROS originating from NOX4 activation may be important in activating microglia in response to neuronal damage via stimulation of p38 MAPK and JNK.”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [157]
In the citing paper
“Whilst the ROS generated here are believed to originate from NOX4 expression, the specificity of apocynin for NOX4 has been questioned [157].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [157]
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Metadata
- Authors
- Wind, S., Beuerlein, K., Eucker, T., Müller, H., Scheurer, P., Armitage, M., Ho, H., Schmidt, H., & Wingler, K.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- Vasopharm (Germany) (DE)
- Florey Institute of Neuroscience and Mental Health (AU)
- ORCID
- Wind, S
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2010-06-17
- Volume
- 161
- Issue
- 4
- Pages
- 885-898
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC2970907
- OpenAlex
- W1736337862
- Cited by
- 241
- References
- 50
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 13 · 2022: 8 · 2021: 10 · 2020: 12 · 2019: 7 · 2018: 13 · 2017: 16 · 2016: 23 · 2015: 23 · 2014: 28 · 2013: 29 · 2012: 31
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Deutsche Forschungsgemeinschaft (SFB-547)
- Bayerische Forschungsstiftung
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology (medical) › 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
- NADPH oxidase inhibitors, reactive oxygen species, oxidative stress, diphenyleneiodonium, apocynin, AEBSF, xanthine oxidase inhibition, eNOS inhibition, spontaneously hypertensive rats, aorta
- MeSH terms
- Acetophenones, Animals, Aorta, Cell Line, Enzyme Inhibitors, Humans, Onium Compounds, Pyrimidines, Rats, Inbred SHR, Rats, Inbred WKY, Sulfones, Triazoles, Reactive Oxygen Species, Oxidative Stress, HL-60 Cells, Caco-2 Cells, NADPH Oxidases, Rats
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