The NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Isoforms are designated NOX1, NOX2, NOX3, and NOX4.
It is made up of six subunits. These subunits are:
- a Rho guanosine triphosphatase (GTPase), usually Rac1 or Rac2 (Rac stands for Rho-related C3 botulinum toxin substrate)
- Five "phox" units. (Phox stands for phagocytic oxidase.)
NADPH oxidase generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce superoxide anion, a reactive free-radical. Superoxide can be produced in phagosomes, which contain ingested bacteria and fungi, or it can be produced outside of the cell. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).
Superoxide kills bacteria and fungi by mechanisms that are not yet fully understood (see article on superoxide), but may inactivate critical metabolic enzymes, initiate lipid peroxidation, and liberate redox-active iron, which allows the generation of indiscriminate oxidants such as the hydroxyl radical. It is presumed that superoxide kills bacteria directly, as the virulence of many pathogens is dramatically attenuated when their superoxide dismutase (SOD) genes are deleted. However, downstream products of superoxide also include hydrogen peroxide and hypochlorous acid, the reactive agent in bleach.
- NADPH + 2O2 ↔ NADP+ + 2O2− + H+
Role in pathology
NADPH oxidase is a major cause of atherosclerosis, and NADPH oxidase inhibitors may reverse atherosclerosis. Atherosclerosis is caused by the accumulation of macrophages containing cholesterol (foam cells) in artery walls (in the intima). NADPH oxidase produces ROSs. These ROSs activate an enzyme that makes the macrophages adhere to the artery wall (by polymerizing actin fibers). This process is counterbalanced by NADPH oxidase inhibitors, and by antioxidants. An imbalance in favor of ROS produces atherosclerosis. In vitro studies have found that the NADPH oxidase inhibitors apocynin and diphenyleneiodonium, along with the antioxidants N-acetyl-cysteine and resveratrol, depolymerized the actin, broke the adhesions, and allowed foam cells to migrate out of the intima.
Mutations in the NADPH oxidase subunit genes cause several Chronic Granulomatous Diseases (CGD), such as
- X-linked chronic granulomatous disease (CGD)
- autosomal recessive cytochrome b-negative CGD
- autosomal recessive cytochrome b-positive CGD type I
- autosomal recessive cytochrome b-positive CGD type II.
In these diseases, cells have a low capacity for phagocytosis, and persistent bacterial infections occur. Areas of infected cells are common, granulomas. A similar disorder called neutrophil immunodeficiency syndrome is linked to a mutation in the RAC2, also a part of the complex.
One study suggests a role for NADPH oxidase in ketamine-induced loss of neuronal parvalbumin and GAD67 expression. Similar loss is observed in schizophrenia, and the results may point at the NADPH oxidase as a possible player in the pathophysiology of the disease. Nitro blue tetrazolium is used in a diagnostic test, in particular, for chronic granulomatous disease, a disease in which there is a defect in NADPH oxidase; therefore, the phagocyte is unable to make the reactive oxygen species or radicals required for bacterial killing, resulting in bacteria thriving within the phagocyte. The higher the blue score the better the cell is at producing reactive oxygen species.
It has also been shown that NADPH oxidase plays a role in the mechanism that induces the formation of sFlt-1, a protein that deactivates certain proangiogenic factors that play a role in the development of the placenta, by facilitating the formation of reactive oxygen species, which are suspected intermediaries in sFlt-1 formation. These effects are in part responsible for inducing pre-eclampsia in pregnant women 
NADPH oxidase can be inhibited by apocynin and DPI (diphenylene iodonium). Apocynin prevents the assembly of the NADPH oxidase subunits. Using apocynin to inhibit NADPH oxidase may have clinical benefits in the treatment of influenza as it lessens influenza-induced lung inflammation in mice in vivo. The most advanced NADPH oxidase inhibitor is GKT-831 (Formerly GKT137831), a first-in-class dual Inhibitor of isoforms NOX4 and NOX1. The compound was invented by Dr. Patrick Page and his team, and was patented in 2007 by Genkyotex. The compound was initially developed for Idiopathic pulmonary fibrosis and obtained orphan drug designation both by FDA and EMEA by end of 2010.
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- Tom Fagan. Does Oxidative Stress Link NMDA and GABA Hypotheses of Schizophrenia? Schizophrenia Research Forum. December 09, 2007. Available at http://www.schizophreniaforum.org/new/detail.asp?id=1413. Accessed December 11, 2007.
- Placenta. 2013 Dec;34(12):1177-82. doi: 10.1016/j.placenta.2013.09.017. Epub 2013 Oct 2.
- Vlahos, Ross; John Stambas; Steven Bozinovski; Brad R. S. Broughton; Grant R. Drummond; Stavros Selemidis (2011-02-03). Schultz-Cherry, Stacey, ed. "Inhibition of Nox2 Oxidase Activity Ameliorates Influenza A Virus-Induced Lung Inflammation". PLoS Pathog. 7 (2): e1001271. PMC . PMID 21304882. doi:10.1371/journal.ppat.1001271.
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- Aoyama, Tomonori; Paik, Yong-Han; Watanabe, Sumio; Laleu, Benoît; Gaggini, Francesca; Fioraso-Cartier, Laetitia; Molango, Sophie; Heitz, Freddy; Merlot, Cédric (2012-12-01). "Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent". Hepatology. 56 (6): 2316–2327. ISSN 1527-3350. PMC . PMID 22806357. doi:10.1002/hep.25938.
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