NADPH Oxidase as a Therapeutic Target for Oxalate Induced Injury in Kidneys

Table 1

Inhibitors of NADPH oxidase.

Name	Mode of action	Pharmacological effects	References
Apocynin	NADPH oxidase complex assembly inhibitor: inhibits binding of p47phox with membrane bound p22phox	Scavenger of H2O2	[130–132]
DPI	Inhibitor of flavoprotein, takes electrons from FAD and prevents electron flow through the flavocytochrome channel	Inhibitor of NADH-ubiquinone oxidoreductase, NADH dehydrogenase, xanthine oxidase, cytochrome p450 oxidoreductase, NOS, and bacterial nicotine oxidase	[133–139]
AEBSF	Inhibits association of NOX2 subunit with p47phox. Prevents binding of p47phox and p67phox with cytochrome b559	Irreversible serine protease inhibitor	[140]
Plumbagin	Inhibits O2^−• production in various cell lines expressing NOX4 oxidase; unknown mechanism	Naphthoquinone structure may confer ROS-scavenging effects	[141, 142]
PR-39	Inhibits p47phox from binding to p22phox subunit by cohering to SH3 domains of p47pphox	Non selective for NADPH oxidase	[143]
S17834	Flavonoid derivative proposed to directly inhibit NADPH oxidase activity, although the mechanism is undefined	None	[144]
VAS2870	Undefined mechanism: inhibits NADPH oxidase activity in NOX2 oxidase-containing HL-60 cell line and in vascular endothelial cells containing NOX2 and NOX4 oxidases; does not scavenge O2^−•	None	[145, 146]
Gp91dstat	Oxidase assembly inhibitor: inhibits association of Nox2 with p47phox. Does not scavenge superoxide generated by cell-free systems	None	[147, 148]
Statins	Decrease superoxide production by inhibiting synthesis of farnesylpyrophosphate and geranylgeranylpyrophosphate which are crucial for membrane attachment of Rac and NADPH oxidase assembly. May also decrease p22phox and Nox1 expression. Likely to influence Nox1 and Nox2 activities	HMG-CoA reductase inhibitor. Decreases AT1 receptor expression; increases eNOS expression, most effective for treating cardiovascular disease with questionable benefit in those without previous CVD but with elevated cholesterol levels	[149, 150]
AT1 receptor antagonists	Decrease Ang II-dependent activation of NADPH oxidase via AT1 receptors. Unlikely to display Nox selectivity as Ang II stimulates Nox1 and Nox4 oxidases	None. Controlling high blood pressure	[151]
Nebivolol	Inhibits membrane association and also interaction of p67phox and Rac and decreases oxidase expression. Inhibits Nox1-dependent superoxide production	β-adrenoceptor blocker, used in treatment of hypertension	[152–155]
Gliotoxin	A fungal metabolite, thiol-modifying toxin thought to inhibit phosphorylation of p47phox by preventing PKC colocalization with p47phox. Also, inhibits electron transport through the flavocytochrome before oxidase activation. Low potency for blocking Nox4	Stimulation of cGMP release. Cytoskeletal reorganization. Disrupts the mitochondrial membrane potential, possesses immunosuppressive properties, anti-inflammatory activity.	[75, 156–160]
Clostridium difficile toxin B	Glycosylation of threonine-35 on Rac, which modifies GTPases activity	Likely to inhibit all Rac-dependent protein activity. High toxicity, vascular permeability and inflammation	[161]
Nordihydroguaia-retic acid	Blocks H2O2 production in macrophages in response to phorbol esters and in endothelial cells in response to thrombin	Lipooxigenase inhibitor. Blocks arachidonic acid metabolism	[162–164]
SKF525A	Decreases superoxide and H2O2 production in endothelial cells	Cytochrome P450 inhibitor	[162, 165]
Metformin	Scavenges hydroxyl radicals but not superoxide. Could also inhibit PMA and Ang II-dependent ROS production from NADPH oxidase. However, this is likely to be due to inhibition of PKC activity	Antihyperglycemic agent. PKC inhibitor	[166–168]
Sildenafil-citrate	Inhibitor of endothelial superoxide production and gp91phox expression	Inhibits phosphodiesterase type 5. Nonselective and in direct inhibitor for NADPH oxidase isoforms. Have been shown to influence immune system due to changes in gp91phox expression	[169–172]
Bilirubin	Inhibitor of superoxide production. No effect on Nox2, p22phox and p47phox but may reduce p47phox phosphorylation	ROS scavenger	[173–175]
Minocycline	Downregulates p67phox expression. Inhibitor of superoxide generation in microglia and dopaminergic neurons in response to stimuli such as thrombin	Antibiotic	[176, 177]
Perhexiline	Inhibits superoxide production in intact neutrophils stimulated by fMLP or PMA. Mechanism unknown	Efficient antianginal agent that blocks carnitine-palmitoyl-transferase	[178, 179]
Roxithromycin	Inhibits superoxide generated by intact neutrophils activated by fMPL or PMA but not by cell lysates. No effect on PKC-dependent phosphorylation. May inhibit translocation of p47phox and/or p67phox	Macrolide antibiotic. Inhibit RNA-dependent protein synthesis. Efficient in blocking cytochrome P450	[180–182]
Taurine chloramines	Inhibits translocation of p47phox and p67phox to the membrane. Also inhibits phosphorylation of p47phox. Reversible inhibition of PMA-dependent superoxide anion production in human neutrophils	Blocks inducible NOS in alveolar macrophages	[183, 184]
Resveratrol	Reduces superoxide generation in intact macrophages and homogenates. Does not scavenge superoxide in cell-free systems	Inhibitor of PKC	[185–187]
Curcurmin	Reduces superoxide production in intact macrophages and homogenates. Does not scavenge superoxide in cell-free systems	Irreversible inhibitor of thioredoxin reductase via alkylation of cysteine residues	[185, 188]
Nitrolinoleate	Nitrated lipid which blocks PMA- and FMLP-dependent superoxide generation and degranulation in human neutrophils by enhancing cAMP but not cGMP levels	Also linked with increasing cAMP vasorelaxation	[189, 190]
Mycophenolate acid	Fungal derivative that blocks endothelial and neutrophil-derived superoxide by reducing Rac levels. Does not alter mRNA levels of Nox2, Nox4, and p47phox	Efficient inhibitor of inosine monophosphate dehydrogenase associated with purine synthesis in B and T lymphocytes	[191, 192]
GK-136901	Well known NOX1 and NOX4 oxidase inhibitor. Unknown mechanism, but structural similarity with NADPH suggests that it may act as a competitive substrate inhibitor of this enzyme	None	[193, 194]
ML171	Phenothiazine compound with selectivity for NOX1 oxidase (IC50 of 0.25 μM) over other NADPH oxidases (IC50 > 3 μM). Does not scavenge oxygen radicals generated by xanthine oxidase activity	None	[195]
Mastoparan	Inhibits superoxide production by neutrophil lysates most likely via interaction with N-terminal of p67phox	An amphiphilic cationic tetradecapeptide isolated from wasp venom. Has affinity towards SH3 domains. Also interact with G-proteins	[196–199]
Ghrelin	Blocks superoxide production by thoracic aorta most probably via release of NO. Does not scavenge superoxide	Capable of releasing growth hormone releasing peptide. Stimulates gastric acid secretion	[200–202]
Alpha tocopherol	Inhibitor of p67phox-p47phox translocation and p47phox phosphorylation in monocytes, neutrophils and microglial cells. This effect is likely to be due to PKC inhibition	ROS scavenger	[203–206]
Benzylisothiocyanate	Concentration-dependent. Inhibits TPA-induced superoxide production in a human leukemia cell line. Does not affect PKC activity and p47phox translocation. Mechanism may involve covalent cysteine modification of the NADPH oxidase	May inhibit NO, PGE2 and TNF-α production. Also known to cause apoptosis via induction of Bak and Bax proteins	[207–209]
Probucol	Known to reduce superoxide production in rabbit aorta, by down-regulation of p22phox	Free radical scavenger	[54, 210–213]
Nox2ds-tat	Oxidase assembly inhibitor: inhibits association of NOX2 subunit with p47phox. Does not scavenge O2^−• generated by cell-free systems	None	[148, 214]
VAS3947	Triazolopyrimidine that decreased ROS production in several cell lines with low micro molar efficiency, irrespective of the specific isoforms expressed; showed no inhibitory effects against xanthine oxidase-derived ROS or eNOS activity	None	[215]

Adapted from [125, 216].
eNOS: endothelial nitric oxide synthase; IC₅₀: half-maximal inhibitory concentration; Nox: NADPH oxidase; O₂^−•: superoxide; ROS: reactive oxygen species; SH3: Src homology 3; DPI: diphenyleneiodonium chloride; AEBSF: 4-(2-aminoethyl)-benzenesulfonyl fluoride; S178341: 4-dimethyl-2,3,5,6-triiodobenzene; VAS-2870: 3-benzyl-7-(2-benzoxazolyl) thio-1,2,3-triazolo (4,5-d) pyrimidine; SKF 525A: 2-diethylaminoethyl 2:2–diphenylvalerate hydrochloride.