Inhibitor superoxide

Takeuchi, K., Nishiwaki, H., Niida, H., Ueshima, K. and Okabe, S. (1991b). Duodenal ulcers induced by diethyl-dithiocarbamate, a superoxide dismutase inhibitor, in the rat role of antioxidative system in the pathogenesis. Jpn. J. Pharmacol. 57, 299-310. 

The antiulcer agent rebamipide ((2-(4-chlorobenzoy-lamino)-3-[2(lH)-quinolinon-4-yl]propionic acid) dose-dependently decreased hydroxyl radical signal generated by the Fenton reaction in an e.s.r. study. Rebamipide is active as a hydroxyl radical scavenger and inhibitor of superoxide production by neutrophils (Yoshikawa etal., 1993). 

In Malaysia, a paste of the roots is applied to fingers to treat eruptions. The plant is known contain some sesquiterpene lactones including neolinderane, zeylanine, zey-lanicine and zeylanidine (59-61), the potential of which as an inhibitor of NOS would be worth investigation because pseudoneolinderane and linderalactone inhibited the production of superoxide anion generation by human neutrophils in response to fMLP/CB. The IC50 values for pseudoneolinderane and linderalactonewere 3.21 and 8.48 (xg/mL, respectively (62). 

B.L. Stoddard, D. Ringe, and G.A. Petsko, The structure of iron superoxide dismutase from Pseudomonas ovalis complexed with the inhibitor azide. Protein Eng. 4, 113-119 (1990). 

At the beginning only XO and not XDH was considered as a superoxide producer. For example, in 1985 McCord [19] suggested that the conversion of XDH into XO is responsible for an increase in superoxide production in postischemic reperfusion injury. However, it has later been shown [20,21] that XDH itself is a producer of superoxide although not so effective as XO. Moreover, the efficiency of superoxide production differs for different types of the enzyme. Thus, 2.8 to 3.0 mol of superoxide were produced by chicken liver XDH, while superoxide production by bovine milk XDH was insignificant [21]. Sanders et al. [22] found that NADH oxidation by human milk and by bovine milk XDHs catalyzed superoxide production more rapidly than XO this process was inhibited by NAD and diphenyleneiodo-nium but not by the established XO inhibitors allopurinol and oxypurinol. 

Two forms of xanthine oxidoreductase namely XO and XDH are present in many human and animal cells and plasma, XDH and XO are the predominant species in cytoplasma and serum, respectively [39]. Damaging effects of XO-catalyzed superoxide production in post-ischemic tissues were demonstrated by many authors. For example, Chambers et al. [40] and Hearse et al. [41] have shown that the suppression of superoxide production by the administration of XO inhibitor allopurinol or SOD resulted in the reduction of infarct size in the dog and of the incidence of reperfusion-induced arrhythmia in the rat. Similarly, Charlat et al. [42] has also shown that allopurinol improved the recovery of the contractile function of reperfused myocardium in the dog. However, the use of allopurinol as the XO inhibitor has been questioned because this compound may affect oxygen radical formation not only as a XO inhibitor but as well as free radical scavenger [43]. Smith et al. [44] also showed that gastric mucosal injury depends on the oxygen radical production catalyzed by XO and iron. 

Holland et al. [125] have shown that the potent vascular smooth muscle cell mitogen and phospholipase A2 activator thrombin stimulated superoxide production in human endothelial cells, which was inhibited by the NADPH oxidase inhibitors. Similarly, thrombin enhanced the production of oxygen species and the expression of )Alphos and Rac2 subunits of NADPH oxidase in VSMCs [126,127]. Greene et al. [128] demonstrated that the activator of NO synthase neuropeptide bradykinin is also able to stimulate NADPH oxidase in VSMCs. Similar to XO, NADPH oxidase enhanced superoxide production in pulmonary artery smooth muscle cells upon exposure to hypoxia [129]. 

Despite a long-time studying of superoxide production by mitochondria, an important question is still debated does mitochondria produce superoxide under physiological conditions or superoxide release is always a characteristic of some pathophysiological disorders resulting in the damage of normal mitochondrial functions Uncertainties in this question arise due to the different results obtained with the use of respiratory inhibitors and different analytical methods. 

Usually, mitochondrial superoxide production is registered only after the incubation of submitochondrial particles with respiratory inhibitors, first of all, rotenone and antimycin. Under such conditions, superoxide production may achieve about 1 nmol 1 1 min 1 per mg of... 

Calcium oxalate monohydrate responsible for the formation of most kidney stones significantly increased mitochondrial superoxide production in renal epithelial cells [42], Recombinant human interleukin IL-(3 induced oxygen radical generation in alveolar epithelial cells, which was suppressed by mitochondrial inhibitors 4 -hydroxy-3 -methoxyacetophe-none and diphenylene iodonium [43]. Espositio et al. [44] found that mitochondrial oxygen radical formation depended on the expression of adenine nucleotide translocator Anti. Correspondingly, mitochondria from skeletal muscle, heart, and brain from the Antl-deficient mice sharply increased the production of hydrogen peroxide. 

Skulachev [117] proposed that the released cytochrome c oxidizes superoxide and, by this, exhibits an antioxidant function. This proposal was supported by recent experimental findings by Atlante et al. [118], who suggested that cytochrome c released from mitochondria by oxygen species protected mitochondria through a feedback-like process oxidizing superoxide. The most important physiological inhibitor of apoptosis is multifunctional protein Bcl-2,... 

Flavonoid baicalein, which is believed to be one of the most important components of Japanese Kampo (traditional herbal) medicine, was found to be an effective scavenger of superoxide and hydroxyl radicals and the inhibitor of iron-induced in vivo lipid peroxidation in gerbils [122],... 

In 1989, we showed [142] that the Fe2+(rutin)2 complex is a more effective inhibitor than rutin of asbestos-induced erythrocyte hemolysis and asbestos-stimulated oxygen radical production by rat peritoneal macrophages. Later on, to evaluate the mechanisms of antioxidant activities of iron rutin and copper-rutin complexes, we compared the effects of these complexes on iron-dependent liposomal and microsomal lipid peroxidation [165], It was found that the iron rutin complex was by two to three times a more efficient inhibitor of liposomal peroxidation than the copper-rutin complex, while the opposite tendency was observed in NADPH-dependent microsomal peroxidation. On the other hand, the copper rutin complex was much more effective than the iron rutin complex in the suppression of microsomal superoxide production, indicating that the copper rutin complex indeed acquired additional SOD-dismuting activity because superoxide is an initiator of NADPH-dependent... 

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