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PubMed1995

Inhibition of redox cycling of methoxatin (PQQ), and of superoxide release by phagocytic white cells.

The iodonium compounds diphenyleneiodonium and diphenyliodonium, and the amine compounds, 4,5-dimethyl phenylene diamine, N,N-dimethyl 1,4-phenylene diamine, 1,2-diamino-4,5-methyleneoxybenzene, and aminomalononitrile inhibit methoxatin's (PQQ's) redox activity in vitro, that is, the methoxatin-coupled oxidation of glycine and reduction of nitroblue tetrazolium to formazan. The compounds mentioned above also inhibit phorbol myristate acetate (PMA) stimulated superoxide release by phagocytic white cells--determined mainly as the superoxide dismutase sensitive reduction of ferricytochrome C. Related compounds, 3,4-diaminopyridine and 4-dimethylamino-benzylamine, did not inhibit redox activity of PQQ in vitro, nor did they inhibit PMA stimulated superoxide production in monocytes or neutrophils. Thus, there is a correlation between an agent's ability to inhibit PQQ redox cycling and its ability to inhibit superoxide release by phagocytes. The findings are a further indication that PQQ is involved in the respiratory burst of phagocytic cells.

Amines↗
PubMed2002

Novel FMN-containing rotenone-insensitive NADH dehydrogenase from Trypanosoma brucei mitochondria: isolation and characterization.

A rotenone-insensitive NADH dehydrogenase has been isolated from the mitochondria of the procyclic form of African parasite, Trypanosoma brucei. The active form of the purified enzyme appears to be a dimer consisting of two 33-kDa subunits with noncovalently bound FMN as a cofactor. Hypotonic treatment of intact mitochondria revealed that the NADH dehydrogenase is located in the inner membrane/matrix fraction facing the matrix. The treatment of mitochondria with increasing concentrations of digitonin suggested that the NADH dehydrogenase is loosely bound to the inner mitochondrial membrane. The NADH:ubiquinone reductase activity is insensitive to rotenone, flavone, or dicumarol; however, it was inhibited by diphenyl iodonium in a time- and concentration-dependent manner. Maximum inhibition by diphenyl iodonium required preincubation with NADH to reduce the flavin. More complete inhibition was obtained with the more hydrophobic electron acceptors, such as Q(1) or Q(2), as compared to the more hydrophilic ones, such as Q(0) or dichloroindophenol. Kinetic analysis of the enzyme indicated that the enzyme followed a ping-pong mechanism. The enzyme conducts a one-electron transfer and can reduce molecular oxygen forming superoxide radical.

Animals↗
PubMed1991

Inhibition of macrophage and endothelial cell nitric oxide synthase by diphenyleneiodonium and its analogs.

The cofactor requirements of macrophage nitric oxide (NO.) synthase suggest involvement of an NADPH-dependent flavoprotein. This prompted us to test the effect of the flavoprotein inhibitors diphenyleneiodonium (DPI), di-2-thienyliodonium (DTI), and iodoniumdiphenyl (ID) on the NO. synthases of macrophages and endothelium. DPI, DTI, and ID completely inhibited NO. synthesis by mouse macrophages, their lysates, and partially purified macrophage NO. synthase. Inhibition of NO. synthase by these agents was potent (IC50's 50-150 nM), irreversible, dependent on time and temperature, and independent of enzyme catalysis. The inhibition by DPI was blocked by NADPH, NADP+, or 2'5'-ADP, but not by NADH. Likewise, FAD or FMN, but not riboflavin or adenosine 5-diphosphoribose, protected NO. synthase from inhibition by DPI. Neither NADPH nor FAD reacted with DPI. Once NO. synthase was inhibited by DPI, neither NADPH nor FAD could restore its activity. DPI also inhibited acetylcholine-induced relaxation of norepinephrine-preconstricted rabbit aortic rings (IC50 300 nM). Inhibition of acetylcholine-induced relaxation persisted for at least 2 h after DPI was washed out. In contrast, DPI had no effect on norepinephrine-induced vasoconstriction itself nor on vasorelaxation induced by the NO.-generating agent sodium nitroprusside. These results suggest that NO. synthesis in both macrophages and endothelial cells depends on an NADPH-utilizing flavoprotein. As a new class of NO. synthase inhibitors, DPI and its analogs are likely to prove useful in analyzing the physiologic and pathophysiologic roles of NO(.).

Amino Acid Oxidoreductases↗
PubMed1997

Changes in host cell energetics in response to bacteriophage PRD1 DNA entry.

Double-stranded DNA bacteriophage PRD1 infects a variety of gram-negative bacteria harboring an IncP-type conjugative plasmid. The plasmid codes for the DNA transfer phage receptor complex in the cell envelope. Our goal was, by using a collection of mutant phage particles for which the variables are the DNA content and/or the presence of the receptor-binding protein, to obtain information on the energy requirements for DNA entry as well as on alterations in the cellular energetics taking place during the first stages of infection. We studied the fluxes of tetraphenylphosphonium (TPP+), phenyldicarbaundecaborane (PCB-), and K+ ions as well as ATP through the envelope of Salmonella typhimurium cells. The final level of the membrane voltage (delta psi) indicator TPP+ accumulated by the infected cells exceeds the initial level before the infection. Besides the effects on TPP+ accumulation, PRD1 induces the leakage of ATP and K+ from the cytosol. All these events were induced only by DNA-containing infectious particles and were cellular ATP and delta psi dependent. PRD1-caused changes in delta psi and in PCB- binding differ considerably from those observed in other bacteriophage infections studied. These results are in accordance with the presence of a specific channel engaged in phage PRD1 DNA transport.

Adenosine Triphosphate↗
PubMed1993

The relationship between sugar metabolism, transport and superoxide radical production in rat peritoneal macrophages.

Dexamethasone inhibits sugar-dependent phorbol myristate acetate (PMA)-stimulated superoxide production and 2-deoxy-D-glucose (2-dGlc) transport in rat peritoneal macrophages (Rist, R.J., Jones, G.E. and Naftalin, R.J. (1991) Biochem. J. 278, 119-128; Rist, R.J. and Naftalin, R.J. (1991) Biochem J. 278, 129-135). Here it is shown that with glucose as a substrate, dexamethasone (0.1 microM) acts as a non-competitive inhibitor of PMA-induced superoxide production; decreasing the maximal rate of superoxide production (P < 0.001) without altering the Km. In contrast, with 2-dGlc as a substrate, dexamethasone shows competitive inhibition of PMA-stimulated superoxide production; increasing the Km of superoxide production, (P < 0.001) without altering the Vmax. The maximal rate of PMA-stimulated superoxide production with glucose as substrate is 10-12-fold in excess of the maximal rate with 2-dGlc as substrate. Diphenylene iodonium (DPI) is a non-competitive inhibitor of PMA-stimulated glucose-dependent superoxide production in macrophages, (Ki = 1-5 microM) and significantly reduces the activity of the PMA-induced hexose monophosphate shunt, (HMPS) (P < 0.01). However, DPI (1 microM) has no significant effect on the PMA-induced increase in 2-dGlc uptake, suggesting that the stimulus for HMPS activity and superoxide production is separate from the stimulus for hexose transport. A model is described which explains the observed differences in hexose transport and glucose- and 2-dGlc-dependent superoxide production in terms of the differences in metabolism of the two sugars. Accumulation of free 2-dGlc within the cytosol leads to saturation of hexokinase and hence, the effects of PMA and dexamethasone, which alter the coupling between hexokinase and the transporter, are only observed at low concentrations of 2-dGlc, where it is accumulated to sub-saturating levels. Since glucose is completely metabolized within the cell, PMA and dexamethasone increase and decrease, respectively, net uptake of sugar and superoxide production at all glucose concentrations.

Animals↗
PubMed1987

The inhibitory effects of some iodonium compounds on the superoxide generating system of neutrophils and their failure to inhibit diaphorase activity.

I have recently reported the inhibition of the neutrophil superoxide generating oxidase by very low concentrations of diphenylene iodonium (A. R. Cross and O. T. G. Jones, Biochem. J. 237, 111, 1986). Here I report on the sensitivity of the oxidase to two other iodonium compounds, iodonium thiophen and iodonium biphenyl. In addition, the lack of inhibition of dye reductase activity in a solubilized preparation of the oxidase is described suggesting that the superoxide forming enzyme system of neutrophils does not possess an intrinsic dye reductase activity.

Animals↗
PubMed1994

Diphenylene iodonium blocks K+ and Ca2+ currents in type I cells isolated from the neonatal rat carotid body.

Diphenylene iodonium (DPI), an inhibitor of NAD(P)H oxidase, blocks hypoxic excitation of the carotid body. We used the whole-cell patch-clamp technique to investigate the actions of DPI on ionic currents in isolated type I carotid body cells. DPI (10 microM) caused reversible blockade of K+ and Ca2+ currents in these cells, indicating that DPI is a non-selective ion channel blocker. Since hypoxic excitation of the carotid body is dependent on Ca2+ influx into type I cells, our observation that DPI blocks Ca2+ currents in type I cells can account for the ability of this compound to inhibit hypoxic excitation of the intact organ.

Animals↗
PubMed2002

Antimalarial activity of yingzhaosu A analogues.

Iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu A analogues 2. In some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting materials. Some of the cyclic peroxides 2 showed significant antimalarial activities in vitro and in vivo.

Animals↗
PubMed2000

The NADPH oxidase inhibitors iodonium diphenyl and cadmium sulphate inhibit hypoxic pulmonary vasoconstriction in isolated rat pulmonary arteries.

Interest surrounds the role of an NADPH oxidase-like enzyme in hypoxic pulmonary vasoconstriction (HPV). We have studied the effects of the NADPH oxidase inhibitors iodonium diphenyl (ID) and cadmium sulphate (CdSO4) upon HPV of isolated rat pulmonary arteries (n = 73, internal diameter 545 +/- 23 microm). Vessels were preconstricted with prostaglandin F2alpha (PGF2alpha, 0.5 or 5 microM) prior to a hypoxic challenge. ID (10 or 50 microM), CdSO4 (100 microM) or vehicle (50 microl) was added for 30 min before re-exposure to PGF2alpha and hypoxia. ID and CdSO4 significantly inhibited HPV. In vessels preconstricted with 5 microM PGF2alpha, ID (10 and 50 microM) reduced HPV from 37.4 +/- 5.6 % to 9.67 +/- 4.4 % of the contractile response elicited by 80 mM KCl (P<0.05) and from 30.1 +/- 5.0 % to 0.63 +/- 0.6% 80 mM KCl response (P<0.01), respectively. CdSO4 (100 microM) reduced HPV from 29.4 +/-4.0 % to 17.1 +/- 2.2% 80 mM KCl response (P<0.05). In vessels preconstricted with 0.5 microM PGF2alpha, ID (10 and 50 microM) reduced HPV from 16.0 +/- 3.15% to 3.36 +/- 1.44 % 80 mM KCl response (P<0.01) and from 15.0 +/- 1.67 % to 2.82 +/- 1.40 % 80 mM KCl response (P<0.001), respectively. Constriction to PGF2alpha was potentiated by ID. ID and CdSO4, at concentrations previously shown to inhibit neutrophil NADPH oxidase, attenuate HPV in isolated rat pulmonary arteries. This suggests that an NADPH oxidase-like enzyme is involved in HPV and could act as the pulmonary oxygen sensor.

Animals↗
PubMed1980

[Study of membrane potential of Bacillus subtilis and Escherichia coli cells by the penetration ions methods].

Using the penetrating ions of tetraphenylphosphonium (TPP+) and tetraphenylborone (TPB-), the membrane potential of the Bacillus subtilis and Escherichia coli cells was shown that the TPP+ absorption by the cells is an energy-coupled process. The TPB- anions are released from the cells after addition of an energy substrate. The value of the membrane potential calculated from the distribution pattern of the penetrating ions in the cells and the incubation medium lies within the interval of --100--150 mV (intracellular negative electric potential). The value of the membrane potential strongly depends on pH of the incubation medium; our attempts to measure the membrane potential in the E. coli cells at ph 6.0 were unsuccessful; however, at pH 8.5 it was found to be equal to --100 mV. Treatment of the cells with nigericin partially prevents the decrease of the membrane potential in an acidic medium and increases the potential in neutral and alkaline media. The formation of the membrane potential is suppressed by valinomycin and gramicidine, as well as by the oxidative phosphorylation uncouplers; the inhibiting effect of valinomycin requires the presence of K+ in the incubation medium. The membrane potential of the B. subtilis cells is insensitive to the effect of cyanide in the absence of arsenate. It is concluded that the membrane potential of B. subtilis and E. coli is formed both via respiration and by hydrolysis of intracellular ATP.

Bacillus subtilis↗
PubMed1996

Osteoclastic superoxide production and bone resorption: stimulation and inhibition by modulators of NADPH oxidase.

Production of superoxide radicals by osteoclasts is necessary for normal bone degradation. White blood cell superoxide, needed for bacterial killing, is produced by activated NADPH oxidase. Since osteoclasts and white blood cells share a common hematopoietic origin, we initiated experiments to test the hypothesis that superoxide radicals at the osteoclast-bone interface are produced by NADPH oxidase. Diphenyl iodonium (IDP), an inhibitor of NADPH oxidase, blocked superoxide generation and decreased osteoclastic bone resorption in cultures of calvarial explants from normal mice. Interferon (IFN) gamma, a stimulant of NADPH oxidase activity, increased superoxide production and bone resorption in cultures of calvarial explants from osteopetrotic (microphthalmic) mice. IDP blocked the stimulatory effects of IFN in this bone resorption model. These data suggest that osteoclastic superoxide is produced by NADPH oxidase.

Animals↗
PubMed1990

Enhancement of transmembrane proton conductivity of protonophores by membrane-permeant cations.

The rate of protonophore-mediated decay of pH gradient across lipid vesicular membranes was found to be enhanced by orders of magnitude by valinomycin-K+. Experiments in the presence of gramicidin have shown that the observed rate enhancement by valinomycin-K+ is not due to collapse of the diffusion potential alone. The enhancement of the rate showed hyperbolic dependence on the concentration of valinomycin. Rate enhancement was observed in the presence of the membrane permeant cation tetraphenylphosphonium (TTP+) also. Several factors which might enhance the intrinsic H+ conductivity of protonophores were analyzed. The level of partitioning of the protonophore into the membrane and the pK of membrane-bound protonophores were measured. Valinomycin-K+ did not alter both these parameters significantly. TPP+ increased the partitioning of protonophores and decreased the pK values of membrane-bound protonophores. However, these changes were too small to explain the observed rate enhancements. We suggest that valinomycin-K+ and TPP+ enhance the H+ conductivity of protonophores by increasing the permeability of the ionized form of protonophores by forming an ion pair.

Boron Compounds↗
PubMed1994

Methoxatin (PQQ) in guinea-pig neutrophils.

PQQ, also called methoxatin, has been isolated from guinea-pig neutrophils. The organic cations diphenyleneiodonium (DPI) and diphenyliodonium (BPI) and the aromatic o-diamine 4,5-dimethylphenylenediamine (DIMPDA) sequester synthetic PQQ and inhibit its redox-cycling activity in a model system. Standards were made of adducts of tritiated PQQ with unlabeled DIMPDA and of unlabeled PQQ with tritiated DPI or DIMPDA. PQQ adducts were isolated from guinea-pig neutrophils with each of the tritiated inhibitors. They were separated and defined by high-performance liquid chromatography (HPLC). Tiron, a disodium benzene disulphonic acid, broke the DPI-PQQ adduct isolated from neutrophils and released free PQQ. Both DPI and DIMPDA, as well as BPI, blocked O2.- release by stimulated neutrophils. The blockade exerted by these inhibitors was released by the addition of PQQ to the cell suspensions. The data demonstrate the presence of PQQ in guinea-pig neutrophils and suggest that it has a possible role, direct or indirect, in the O2.(-)-producing respiratory burst.

Animals↗
PubMed2005

Iron-dependent lysosomal destabilization initiates silica-induced apoptosis in murine macrophages.

Alveolar macrophages play a critical role in silica-induced lung fibrosis, and apoptotic mechanisms have been implicated in silica-induced pathogenesis. Here, employing a model of murine macrophages (J774 cells), it is shown that serum-coated alpha-quartz silica particles cause lysosomal rupture and apoptosis following endocytotic uptake. The loss of lysosomal integrity involves intralysosomal iron-catalyzed peroxidative damage to lysosomal membranes. Thus, lysosomal damage is most pronounced in cells exposed to silica particles with high amounts of surface-bound iron, whereas silica particles previously treated with the iron chelator desferrioxamine only induce modest rupture. Furthermore, inhibition of intralysosomal Fenton type chemistry, either by pre-treatment with desferrioxamine complexed to starch--an iron chelator targeted to the lysosomal compartment--or by concomitant treatment with diphenylene iodonium--a potent inhibitor of NADPH oxidase --both prevent silica-induced lysosomal leakage and ensuing apoptotic cell death. This study also demonstrates that silica-induced lysosomal rupture is a very early apoptotic event, preceding activation of caspases, disruption of transmembrane mitochondrial potential and DNA fragmentation. Indeed, these later apoptotic events appear to be directly correlated to the magnitude of lysosomal leakage, and are not observed in cells treated with high molecular weight desferrioxamine or diphenylene iodonium.

Animals↗
PubMed1991

O2-. release by activated Kupffer cells upon hypoxia-reoxygenation.

Primary cultures of rat liver Kupffer cells generated large amounts of superoxide anion radical (O2-.) when subjected to reoxygenation after a hypoxic period of at least 2 h. O2-. formation reached its maximum rate of approximately 25 nmol/10(6) cells within 1 h after reoxygenation. Two to four hours after reoxygenation, the number of injured cells began to increase and after 10 h approximately 60% of the cells were dead. During the period of O2-. release no significant difference in cell viability was observed between reoxygenated and hypoxically incubated cells, indicating a distinct time lag between O2-. release and onset of cell damage. Addition of diphenyliodonium, a specific inhibitor of the neutrophilic NADPH oxidase, to the Kupffer cells just before reoxygenation diminished both O2-. formation and cell injury up to 70%. Reoxygenation injury was completely prevented when superoxide dismutase and catalase were added immediately before reoxygenation. The results indicate that Kupffer cells subjected to hypoxia-reoxygenation generate a burst of reactive oxygen species and that this kind of "activation," probably by activating the NADPH oxidase, contributes to the self-destruction of the cells.

Animals↗
PubMed2000

Interaction of respiratory burst and uptake of dehydroascorbic acid in differentiated HL-60 cells.

HL-60 cells differentiated with DMSO increased their rates of uptake of ascorbate when they were activated with PMA. The rates observed after this activation were essentially the same as those with dehydroascorbic acid as the original transport substrate. The effect of activation was sensitive to the antioxidant enzymes superoxide dismutase and catalase. When ascorbate was oxidized in situ by chemical or enzymic oxidation, the rates of uptake were similar to those after activation of the cells by phorbol ester; however, in the latter case the extracellular vitamin remained largely in the reduced form and there was very little loss by degradation, whereas after immediate oxidation no more reduced ascorbate could be found outside the cells after a few minutes and a significant part of the total vitamin was lost. The generation of superoxide by xanthine/xanthine oxidase stimulated the uptake of ascorbate much less than the activation by phorbol ester; H(2)O(2) was even less effective. Stimulation of the uptake by phorbol ester was also insensitive to GSH, in contrast with stimulation by the chemical oxidation of ascorbate. Stimulation of ascorbate uptake by phorbol ester was sensitive to the respiratory-burst inhibitor diphenyliodonium as well as the protein kinase C inhibitor staurosporine, indicating the respiratory burst as the cause of stimulation. Activation of the cells by the phorbol ester also stimulated the uptake of dehydroascorbate as the original substrate, in a manner insensitive to antioxidants or inhibitors of the respiratory burst. In all cases the intracellular vitamin was completely in the reduced form. Kinetic characterization by the calculation of maximal velocities and apparent K(m) values and assaying for the dependence of uptake rates on the ionic milieu and for inhibition by glucose analogues and inhibitors of glucose transport revealed that after treatment with phorbol ester the uptake of total vitamin C in differentiated HL-60 cells was largely due to the low-affinity high-capacity glucose transporter. In contrast, in non-stimulated cells reduced ascorbate was taken up by the Na(+)-dependent high-affinity low-capacity ascorbate transporter. This change was probably due to the oxidation of ascorbate and, simultaneously, the recruitment of additional transporter molecules to the cell surface.

Biological Transport↗