Superoxide, also production

Also, AMI and N-substituted indole esters (Fig. 3), which were reported to be COX-2 enzyme inhibitors, have inhibitory activity on LP and superoxide anion production [91]. Especially pyrrolidine and o-methylphenyl groups were found to be the most important side chains (Ri group) that elevated both activities for indole esters. 

Benzene metabolites have also been shown to damage murine hematopoietic cells in vitro (Seidel et al. 1991). In addition, benzene has been shown to decrease mitochondrial respiration and increase superoxide radical production in isolated rat heart mitochondria (Stolze and Nohl 1994). The effects of exposure of HL-60 cells (human promyelocytic leukemic cells) to hydroquinone, />benzoquinonc, or 1,2,4-benzene-triol were studied by Rao and Snyder (1995). The cytotoxic effect of the metabolites on HL-60 cells, measured as cell viability, could be ranked as />benzoquinone>hydroquinone> 1,2,4-benzenetriol, with viability from 50% to 70% after incubation with concentrations up to 100 pM for 4 hours. Basal levels of superoxide anion or nitric oxide production were not affected by incubation of the cells with the metabolites, but in the presence of TPA, each metabolite increased superoxide anion production however, nitric oxide production was increased with hydroquinone and />benzoquinonc, but not 1,2,4-benzenetriol. HL-60 cells showed increased production of hydrogen peroxide after exposure to the three benzene metabolites. This study suggests that benzene metabolites may predispose the cells to oxidative damage by inhibiting or reducing antioxidant mechanisms within the cell. 

Superoxide Ofj production by neutrophils and macrophages is part of the host defenses against microorganisms. PLD has been imphcated in this response because agents that elicit O2 formation also activate PLD [162-164]. In addition, in vitro experiments showed that PA elicited NADPH-dependent O2 formation in neutrophil extracts or intact neutrophils [165, 166]. Some studies also showed a high correlation between O2 production and PA accumulation in neutrophils stimulated with FMLP [167]. Furthermore, treatment of these cells with ethanol decreased both PA formation and O2 generation. 

Mechanisms of action of 30, 31 and 32 were probed in various cell lines. Phthalides 30, 31 and 32 prevented cortical neuronal cell death and inhibited the release of several injury surrogate biomarkers induced by KC1 [335], A -methyl-D-aspartate (NMDA) [335], AA [336] and hypoxia/hypoglycemia [337-339], These effects appeared to be related to an increase in NO and PGI2 release from neuronal [340, 341] and cerebral endothelial cells [342], Phthalides 30, 31 and 32 reduced superoxide anion production in a xanthine-xanthine oxidase reaction system [343]. The three phthalides also decreased intracellular Ca2+ level in cortical neuronal cells [344]. Furthermore, phthalides 30, 31 and 32 ameliorated the abnormal activities of several mitochondrial respiratory chain complexes induced by MCAO [322] and those of mitochondrial ATPase induced by hypoxia/hypoglycemia in cortical neuronal cells [345],... 

Fig 24.23. A model for the role of ROS and RNOS in neuronal degradation in Parkinson s disease. 1. Dopamine levels are reduced by monoamine oxidase, which generates H2O2. 2. Superoxide also can be produced by mitochondria, which SOD will convert to H2O2. Iron levels increase, which allows the Fenton reaction to proceed, generating hydroxyl radicals. 3. NO, produced by inducible nitric oxide synthase, reacts with superoxide to form RNOS. 4. The RNOS and hydroxyl radical lead to radical chain reactions that result in Upid peroxidation, protein oxidation, the formation of lipofuscin, and neuronal degeneration. The end result is a reduced production and release of dopamine, which leads to the clinical symptoms observed. 

CuZn-SOD IgGi immtme complexes induced a Fcy-dependent intracellidar dehvery of the antioxidant enzyme in IFN-y-activated murine J774 macrophages (Vouldoukis et al. 2000). The concomitant stimulation of the Fcy-receptor and the translocation of the SODl in the cytoplasm of IFN-y-activated macrophages not only reduced the production of superoxide anion but also induced the expression of iNOS and the related NO production. This inducing effect in the absence of superoxide anion production reduced mitochondrial damage and cell death by apoptosis and promoted the intracellular antioxidant armature. 

More recently, the metabolism of the ubiquitous cell messenger, nitric oxide ( NO), has been identified as a major target for polyphenols. An interesting example is the inhibition of NADPH oxidase by 3 -0-methyl epicatechin (Steffen et al, 2008), which, by decreasing superoxide radical production, improves the bioactivity of NO in vivo. Also, it has been recently shown (Gago et al., 2007) that polyphenols from red wine are efficient catalyzers of nitrite reduction to NO in the gastric compartment and this constitutes a large source of "NO independent of its enzymatic synthesis from nitric oxide synthases. 

Unsymmetrical thiosulphinates and thiosulphonates are both oxidized by potassium superoxide in pyridine in the presence of 18-crown-6 ether to produce sulphinic and sulphonic acids and a disulphide, under mild conditions (equation 84)200,201. Sulphinic and sulphonic acids were produced from both the R and R substituents whilst the disulphide was derived only from the sulphenyl side of the reactant. Thus, the reaction mixture contained five products, making the reaction not synthetically useful. Pyrolysis of thiosulphinates also produces mixtures of products, one being the thiosulphonate again this is not a synthetically useful reaction202. 

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