Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iodonium inhibition of the flavoenzymes neutrophil NADPH oxidase and cytochrome P450 reductase has been suggested to require reductive metabolism of the inhibitor to a phenyl radical. Inhibition would ultimately result from covalent attachment of phenyl radicals to either the flavin cofactor or adjacent amino acid side chains important in catalysis. In this paper we provide evidence, using EPR techniques, that phenyl radicals are formed during reaction of iodonium diphenyl with reduced free flavin (FMN) and protein-bound (cytochrome P450 reductase or xanthine oxidase) flavin. Kinetic analysis indicated iodonium diphenyl to be an uncompetitive inhibitor of xanthine oxidase, suggesting the need for reduced enzyme for inhibition. A study of the catalytic and structural properties of different flavoenzymes suggested that only enzymes containing flavins that function in one-electron transfer are targets for iodonium inhibition.
Mol Pharmacol 1994 Oct
PMID:Involvement of phenyl radicals in iodonium inhibition of flavoenzymes. 796 60

Reuptake of glutamate in astrocytes, a critical mechanism involved in the maintenance of physiological excitatory amino acid neurotransmission, is inhibited by both arachidonic acid (AA) and reactive oxygen species (ROS), via incompletely defined molecular mechanisms. Because ROS are generated during AA metabolism and AA can be released as a result of ROS-mediated phospholipase A2 activation, it seems likely that their effects on uptake are mediated by a common mechanism. However, here we show that rapid (10-min) uptake inhibitions by AA or by ROS generated by the xanthine plus xanthine oxidase (XO) reaction are selectively abolished by distinct agents; bovine serum albumin (BSA) acts only on AA, whereas the scavenger enzymes superoxide dismutase (SOD) and catalase (CAT) and the disulfide-reducing agent dithiothreitol (DTT) act only on ROS. Moreover, when added together, xanthine/XO and AA decrease uptake in a fully additive manner. In particular, the effect of xanthine/XO is seen also in the presence of maximal AA inhibition. No major signs of cell damage or chemical reaction between AA and radicals accompany their cumulative effects on uptake. Finally, uptake inhibition elicited by AA and xanthine/XO together is attenuated but not blocked by either BSA, DTT, or SOD/CAT individually, whereas it is fully blocked and substantially reversed by a combination of SOD/CAT and BSA or SOD/CAT, DTT, and BSA. Together, these data indicate that AA and ROS act on glial glutamate transport via distinct noninteracting mechanisms. Therefore, they could independently and additively contribute to the impairment of reuptake function, a phenomenon observed in pathological conditions such as ischemia/reperfusion injury.
Mol Pharmacol 1994 Nov
PMID:Glutamate uptake is inhibited by arachidonic acid and oxygen radicals via two distinct and additive mechanisms. 796 90

Xanthine dehydrogenase (XDH) is an important precursor to the oxygen radical producing enzyme xanthine oxidase (XO). We found that the apparent activity of rabbit myocardial XDH increased from 2 +/- 1 to 50 +/- 3 microU/g (P < 0.05) following extraction of tissue homogenate with butanol. Further studies suggested that the basis for this observation was a high molecular weight compound which consumes the XDH cofactor, NAD+. Addition of myocardial homogenate to exogenous NAD+ resulted in depletion of NAD+ and concomitant formation of an additional compound (peak A). Both NAD+ consumption and peak A formation were abrogated by prior extraction of homogenate with butanol. Separation of myocardial homogenate by Sephadex chromatography revealed a high molecular weight compound which suppressed activity of purified milk XDH but not xanthine oxidase (XO). This activity co-eluted with the ability of myocardial homogenate to consume added NAD+ and form peak A. The NAD(+)-consuming activity was heat and acid-labile. In addition, nicotinamide was both a product and an inhibitor of the NADase activity, consistent with the existence of a previously described myocardial glycohydrolase. Extraction of tissue with butanol may be necessary to detect low levels of XDH activity in vitro.
J Mol Cell Cardiol 1994 Feb
PMID:Suppression of rabbit myocardial xanthine dehydrogenase activity by an endogenous compound. 800 74

To determine whether hydroxyl radicals (.OH) are generated in the hypoxanthine (HPX)-xanthine oxidase (XOD) reaction, we examined the electron paramagnetic resonance (EPR) spectra of the spin adducts formed. In the EPR study, we used 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin trap, sodium formate (HCOONa) as a .OH scavenger, and oxygen-17 gas as an oxygen source. In the HPX-XOD reaction, both M4PO-OOH and M4PO-OH were observed in the reaction products. The formation of M4PO-OH was independently inhibited by HCOONa resulting in the formation of M4PO-CO2- and in no effects on the formation of M4PO-OOH. With oxygen-17 gas as an oxygen source in the HPX-XOD reaction, both M4PO-17OOH and M4PO-17OH were observed in the reaction products. These results indicate that M4PO-OH is not produced by decomposition of M4PO-OOH and .OH is actually generated during the HPX-XOD reaction.
Biochem Mol Biol Int 1994 Mar
PMID:Use of M4PO and oxygen-17 in the study on hydroxyl radical generation in the hypoxanthine-xanthine oxidase reaction. 803 19

The presence of cancer induces metabolic alterations in distant, tumor-free tissues and organs of the host. A remote humoral effect of cancer growing extrahepatically is an increase in the activity of oxidant and a decrease of antioxidant enzymes in the liver of the tumor-bearing animal. We speculated that TNF-alpha, produced by host cells, the cancer, or both, is responsible for these changes. When human recombinant TNF-alpha, 100 micrograms/kg/d i.p. for 5 days, was injected in groups of rats fed ad libitum, starved, or pair-fed, a decrease in the activity of superoxide dismutase and glutathione peroxidase and an increase in xanthine oxidase was observed, particularly with pair-fed controls. It is concluded that TNF-alpha, directly or indirectly, causes these enzyme alterations in the tumor-free liver of a tumor-bearing host.
Biochem Mol Biol Int 1994 May
PMID:TNF-alpha effect on oxygen free radical scavenging and generating enzymes in rat liver. 808 Dec 9

Hypoxanthine is present in preparations of follicular fluid and has been shown to suppress the spontaneous meiotic maturation of mammalian oocytes in vitro. The present experiments examined the possible role of hypoxanthine metabolism in mediating this meiotic arrest. Four putative inhibitors of the enzyme, hypoxanthine phosphoribosyltransferase (HPRT), which metabolizes hypoxanthine to inosine monophosphate, were tested on lysates of oocyte-cumulus cell complexes. At a concentration of 1 mM, 6-mercapto-9-(tetrahydro-2-furyl)-purine (MPTF) and 6-mercaptopurine (6-MP) suppressed enzymatic activity by 86% and 98%, respectively, while 6-azauridine and 2,6-bis-(hydroxyamino)-9-beta-D-ribofuranosyl-purine had no effect. MPTF and 6-MP increased the inhibitory effect of hypoxanthine on germinal vesicle breakdown, but the other agents did not. The 2 active agents had similar effects on salvage activity and hypoxanthine-maintained meiotic arrest in denuded oocytes. Also, oocytes from XO mice were more sensitive to the meiosis-arresting action of hypoxanthine than oocytes from XX littermates, which have twice the HPRT activity. The actions of the HPRT inhibitors were not due to their conversion to nucleotides via HPRT and negative feedback on purine de novo synthesis, because azaserine and 6-methylmercaptopurine riboside, which are more potent inhibitors of de novo synthesis, had a stimulatory, rather than inhibitory, effect on hypoxanthine-arrested oocytes. Furthermore, several lines of evidence indicate that metabolism of hypoxanthine to xanthine and uric acid by xanthine oxidase does not mediate the inhibitory action of this purine base on meiotic maturation. The data therefore suggest that nonmetabolized hypoxanthine is responsible for the meiotic arrest observed, most likely through suppression of cAMP degradation.
Mol Reprod Dev 1993 May
PMID:Purine control of mouse oocyte maturation: evidence that nonmetabolized hypoxanthine maintains meiotic arrest. 809 93

One of the current theories of cardiovascular disease is that it may begin with oxygen radical-induced damages. Extensive studies have been made in different laboratories to elucidate the mechanism of oxidative damages in the presence of added iron salts. However, those in vitro studies are unlikely to be relevant to the in vivo situation, where in the normal physiological condition most of the iron remains bound with proteins. In the present study we have demonstrated that an in vitro system containing desferrioxamine, a strong iron chelator, superoxide generated by the action of xanthine oxidase on acetaldehyde initiates lipid peroxidation and protein changes in the guinea pig cardiac microsomes. We have further demonstrated that superoxide-initiated lipid peroxidation and protein changes are completely prevented by ascorbic acid. SOD also prevents but catalase, alpha-tocopherol, glutathione, uric acid, thiourea, mannitol and histidine are without effect. When NADPH is used instead of generated superoxide, the lipid peroxidation and protein changes are exclusively inhibited by ascorbic acid. SOD, catalase and other antioxidants are ineffective. The results obtained with guinea pigs may be extrapolated to humans, because like guinea pigs humans are also incapable of synthesizing ascorbic acid.
Mol Cell Biochem 1993 Sep 08
PMID:Protective effect of ascorbic acid against lipid peroxidation and oxidative damage in cardiac microsomes. 810 91

Using a lysosome-enriched "light mitochondrial" fraction of a rat liver homogenate, the effects of the reactive oxygen species hydrogen peroxide, superoxide- and hydroxyl radicals were determined. Alterations in the intralysosomal pH and the release of a lysosomal marker enzyme, N-acetyl-glucosaminidase, were used as indicators of changes in the lysosomal membrane integrity. Lipid peroxidation of the fraction was assayed by TBARS measurement. Neither superoxide radicals, generated by hypoxanthine/xanthine oxidase, nor a bolus dose of hydrogen peroxide (0.5-1.5 mM) induced any lysosomal damage. If, however, Fe(III)ADP was included in the superoxide radical-generating system, lysosomal membrane damage was detected, both as an increase in lysosomal pH and as a release of N-acetyl-glucosaminidase, but only after a lag phase of about 7 min. Lipid peroxidation, on the other hand, proceeded gradually. Lysosomes treated with hydrogen peroxide displayed similar dose-dependent alterations, albeit only if both Fe(III)ADP and the reducing amino acid cysteine were added. In the latter system, however, alterations of the lysosomal membrane stability occurred more rapidly, showing a lag phase of only 2 min. Lipid peroxidation, which proceeded faster and displayed no lag phase, levelled out within 10 min. The results indicate that neither superoxide radicals nor hydrogen peroxide are by themselves damaging to lysosomes. Available catalytically active iron in Fe(II) form, however, allows reactions yielding powerful oxidative species--probably hydroxyl radicals formed via Fenton reactions--to take place inducing peroxidation of the lysosomal membranes resulting in dissipation of the proton-gradient and leakage of their enzyme contents.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Effect of reactive oxygen species on lysosomal membrane integrity. A study on a lysosomal fraction. 814 62

The effects of surfactant apoprotein A (SP-A) on the superoxide production of rat alveolar macrophages (AM) were studied. Superoxide production was measured by the ferricytochrome c reduction method. When AM were incubated with SP-A only during the measurement of superoxide production, superoxide production was not influenced by SP-A. However, when AM were preincubated with SP-A at a concentration of 1, 2, and 10 micrograms/ml, superoxide production by AM was significantly inhibited (P < 0.05, P < 0.01, P < 0.01, respectively). The superoxide production of AM stimulated by PMA was significantly inhibited by SP-A at a concentration of 1 microgram/ml (P < 0.01), and superoxide production stimulated by zymosan was also inhibited by SP-A at a concentration of 10 micrograms/ml (P < 0.05). Suppression of superoxide production of unstimulated and PMA-stimulated AM was significantly inhibited by anti-SP-A antibody. Superoxide generation by the xanthine and xanthine oxidase system was not affected by the presence of SP-A. Our results suggest that superoxide production of AM can be inhibited by SP-A and that this inhibitory effect on AM is due to a specific effect of SP-A. From these results, it is speculated that SP-A may have a protective role for oxidant injury by AM in the lung.
Am J Respir Cell Mol Biol 1993 Nov
PMID:Rat surfactant apoprotein A (SP-A) exhibits antioxidant effects on alveolar macrophages. 821 93

Isolated rat hepatocytes were used for the evaluation of nucleotide depletion and oxidative stress as two causal components of postischemic injury following oxygen deficiency. The ATP and GTP loss during anoxia was accompanied by temporary increases of nucleotide degradation products. The critical duration of anoxia for a complete ATP restoration during reoxygenation was between 30 and 60 min. The oxidative stress during reoxygenation was demonstrated by decrease of GSH concentration and increase of TBA-RS level. The tremendous GSH loss could not be balanced by the slight GSSG increase during reoxygenation. Prevention of GSH decrease and TBA-RS increase in parallel to prevention of viability loss in presence of oxipurinol in contrast to lacking improvement of ATP and GTP restoration by this drug speak in favor for the oxidative stress as major causal component for postischemic injury of hepatocytes in comparison with depletion of energy-rich purine nucleotides. The inhibition of formation of reactive oxygen species via xanthine oxidase reactions was found to be the dominant protective effect of oxipurinol against postischemic injury of hepatocytes in comparison with lacking influence on nucleotide salvage and ATP/GTP regeneration and with radical scavenging.
Cell Mol Biol (Noisy-le-grand) 1993 Sep
PMID:Reoxygenation injury of rat hepatocytes: evaluation of nucleotide depletion and oxidative stress as causal components. 822 73


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