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At least 19 recordsLinked to original sources
PubMed1978

Effects of 1,10-phenanthroline and a zinc complex of 1,10-phenanthroline on nucleic acid synthesis in mouse liver and spleen.

The effects of 1,10-phenanthroline and a zinc complex of 1,10-phenanthroline on nucleic acid synthesis were examined by noting the capcity of these agents to incorporate [methyl-3H]thymidine, or [5-3H]uridine into hepatic and splenic DNA and RNA. Within 32 hours after the intraperitoneal injection of 1,10-phenanthroline in mice, a decrease of [methyl-3H]thymidine incorporation into hepatic DNA was observed. The administration of the zinc complex of 1,10-phenanthroline decreased the incorporation of [5-3H] uridine into hepatic RNA within 24 hours and decreased the formation of [3H]DNA from [methyl-3H]thymidine in the liver within 24 and 32 hours. An increase of the isotopic incorporation into hepatic RNA and of the pool size of ATP within 2 hours after the administration of the complex was also noted. In the splenic studies, the zinc complex significantly inhibited the formation of labeled DNA and RNA at 2, 8, 24, and 32 and 2, 8 and 24 hours postinjection, respectively. A relationship exists between the results obtained from sequential treatment (zinc chloride after 1,10-phenanthroline) and those derived from the zinc complex of 1,10-phenanthroline pertaining to an inhibition of isotopic incorporation into hepatic and splenic nucleic acid.

Adenine Nucleotides↗
PubMed1977

Teratogenicity of zinc chloride, 1,10-phenanthroline, and a zinc-1,10-phenanthroline complex in mice.

Zinc chloride, in single doses of 12.5, 20.5 and 25 mg/kg ip on Day 8,9,10, or 11 of gestation in CF-1 albino mice, produced skeletal anomalies without accompanying soft tissue defects. Ripple ribs, the most unusual anomaly, first appeared when the zinc salt was given on Day 9 of gestation in a dose of 20.5 mg/kg, becoming more prevalent when 25 mg/kg of the drug was administered on Day 11.1,10-Phenanthroline, in single doses of 30 mg/kg ip on Day 8,9,10, or 11 of gestation elicited skeletal defects comparable to those caused by zinc chloride as well as soft tissue anomalies, but a significant incidence of the former occurred with this agent only following its injection on Day 8 of gestation. A zinc-1,10-phenanthroline complex in single doses of 50 mg/kg on Day 8,9,10, or 11 of gestation yielded significant incidences of skeletal and soft tissue anomalies only when the complex was administered on Day 8 or 9 of gestation. This dosage level was toxic to both the mother and fetus when given on Day 10 of gestation. However, when the complex was given on Day 8,9,10, or 11 in a dose of 25 mg/kg, neither toxic nor teratogenic effects were observed in the mother or fetus, respectively.

Animals↗
PubMed1977

Stimulation of the activity of prolyl hydroxylase in 3T3 fibroblasts by 1,10-phenanthroline.

In confluent cultures of 3T3 fibroblasts, incubated for 24 h with 1,10-phenanthroline at 10(-5)--10(-9) M, the activity of prolyl hydroxylase was significantly increased. 1,10-Phenanthroline was inhibitory at concentrations greater than 10(-4) M. The stimulatory effect of 1,10-phenanthroline manifests itself after 6 h incubation and increased with time up to 48 h. 2,2'-dipyridyl and 5,6-dimethyl-1,10-phenanthroline were also stimulatory; a nonchelating analog, 1,7-phenanthroline had no effect. Cycloheximide did not modify the 1,10-phenanthroline effect. The stimulatory effect does not seem to depend on the shift of an inactive precursor of prolyl hydroxylase to an active form because 1,10-phenanthroline was shown to be ineffective in logarithmically growing cells. While dialysis of washed and homogenized cells significantly increased prolyl hydroxylase activity in cell extracts, undialyzed 1,10-phenanthroline treated samples exhibited higher prolyl hydroxylase activity than dialyzed controls. These data suggested to us that 1,10-phenanthroline and other chelating agents may be forming complexes with certain metal ions or protein-metal ions which are inhibitory towards prolyl hydroxylase.

2,2'-Dipyridyl↗
PubMed1992

Kinetics of the course of inactivation of aminoacylase by 1,10-phenanthroline.

The kinetic theory of the substrate reaction during modification of enzyme activity previously described [Tsou (1988) Adv. Enzymol. Relat. Areas Mol. Biol. 61, 381-436] has been applied to a study on the kinetics of the course of inactivation of aminoacylase by 1,10-phenanthroline. Upon dilution of the enzyme that had been incubated with 1,10-phenanthroline into the reaction mixture, the activity of the inhibited enzyme gradually increased, indicating dissociation of a reversible enzyme--1,10-phenanthroline complex. The kinetics of the substrate reaction with different concentrations of the substrate chloroacetyl-L-alanine and the inactivator suggest a complexing mechanism for inactivation by, and substrate competition with, 1,10-phenanthroline at the active site. The inactivation kinetics are single phasic, showing that the initial formation of an enzyme-Zn(2+)-1,10-phenanthroline complex is a relatively rapid reaction, followed by a slow inactivation step that probably involves a conformational change of the enzyme. The presence of Zn2+ apparently stabilizes an active-site conformation required for enzyme activity.

Amidohydrolases↗
PubMed1977

Action of 1,10-phenanthroline transition metal chelates on P388 mouse lymphocyte leukaemic cells.

(1)Fully coordinated 1,10-phenanthroline and 2,2'-bipyridine chelates of Ru(II) are lethal in vitro to cultured and ascites P388 mouse lymphocytic leukaemic cells; 1,10-phenanthroline chelates are generally more potent than corresponding 2,2'-bipyridine compounds, and mixed-ligand (acetylacetonato) monovalent chelates of both series are more active than the corresponding identical-ligand divalent chelates. Lethal potency is greatest for Ru(II) chelates containing highly alkylated ligands. (2) Within two series of tetramethyl-1,10-phenanthroline chelates, the inert Ru(II) and Ni(II) members are less active against P388 cultured and ascites cells than the corresponding more labile chelates of Cu(II), Cd(II), Zn(II), Fe(II), and Co(II); for the ascites cells, the rank order of lethal potency of the chelates correlates reasonably well with their anticipated rank order of kinetic reactivity. (3) Repeated subculture of P388 cells in the presence of a mixed-ligand Ru(II) chelate has produced a cell line that shows a stable 10-fold resistance to the chelate; the resistant cell line is selectively cross-resistant to certain Ru(II) identical and mixed-ligand chelates. (4) The presence of a fluorescent Ru(II) chelate has been demonstrated at the surface and within the cytoplasm and nucleus of P388 ascites cells exposed to it either in vitro or in the mouse. (5) Ru(II) and Cu(II) chelates of tetramethyl-1,10-phenanthroline do not appear to be chemotherapeutically active against P388 ascites cells in the mouse.

Animals↗
PubMed1992

Interactions of 1,10-phenanthroline and its copper complex with Ehrlich cells.

Mechanistic details of the interaction of 1,10-phenanthroline and its copper complex with Ehrlich ascites tumor cells were examined, using inhibition of cell proliferation, DNA breakage, and increased membrane permeability as indices of cellular damage. The metal chelating agent, 1,10-phenanthroline (OP), the 1:0.5 complex of 1,10-phenanthroline and CuCl2 [(OP)2Cu], and CuCl2 inhibited growth of Ehrlich ascites tumor cell monolayers during 48-h treatments by 50% at about 3.5, 2, and 70 nmol/10(5) cells/mL, respectively. (OP)2Cu at 10 nmol/10(5) cells also enhanced uptake of trypan blue dye during 6 h of treatment, while dye uptake in OP- and CuCl2-treated cells remained similar to controls. DNA breakage, measured by DNA alkaline elution, was produced during 1-h treatments with (OP)2Cu at drug/cell ratios similar to those producing growth inhibition. Copper uptake was similar for both (OP)2Cu and CuCl2. Electron spin resonance (ESR) spectroscopy suggested that cellular ligands bind copper added as (OP)2Cu or CuCl2 and then undergo time-dependent reductions of Cu(II) to Cu(I) for both forms. Inhibition of (OP)2Cu-induced single-strand scission and trypan blue uptake by scavengers of activated oxygen is consistent with participation of superoxide and H2O2 in both processes. In contrast, superoxide dismutase (SOD) did not reduce the magnitude of the fraction of cellular DNA appearing in lysis fractions prior to alkaline elution of (OP)2Cu-treated cells. Dimethyl sulfoxide (DMSO) inhibited uptake of trypan blue dye but did not inhibit DNA strand scission produced by (OP)2Cu. Thus, multiple mechanisms for generation of oxidative damage occur in (OP)2Cu-treated cells. Growth inhibition produced by OP or (OP)2Cu, as well as the low levels of strand scission produced by OP, was not reversed by scavengers.

Animals↗
PubMed1977

The reactions of 1,10-phenanthroline with yeast alcohol dehydrogenase.

Freshly prepared samples of yeast alcohol dehydrogenase (EC 1.1.1.1) were inhibited by 1,10-phenanthroline at pH 7.0 and 0 degrees C in a two-stage process. The first step appeared to be slowly established, but was rendered reversible by removal of reagent or by addition of excess Zn2+ ions. The second step was irreversible and was associated with the dissociation of the tetrameric enzyme. The presence of saturating concentrations of NAD+ or NADH promoted and enhanced inhibition by the slowly established reversible process, but prevented dissociation of the enzyme. For the incubation mixtures containing NAD+, removal of the 1,10-phenanthroline resulted in virtually complete recovery of activity, whereas, for the incubation mixtures containing NADH, removal of the reagent gave only partial re-activation. The presence of NAD+ and pyrazole, or NADH and acetamide, in incubation mixtures with the enzyme gave rise to ternary complexes that gave protection against both forms of inactivation by 1,10-phenanthroline. The results support the view that at least some of the Zn2+ ions associated with yeast alcohol dehydrogenase have a catalytic, as opposed to a purely structural, role.

Alcohol Oxidoreductases↗
PubMed1991

Sequence selective binding to the DNA major groove: tris(1,10-phenanthroline) metal complexes binding to poly(dG-dC) and poly(dA-dT).

Molecular modelling and energy minimisation calculations that incorporate solvent effects have been used to investigate the complexation of delta and lambda-[Ru(1,10-phenanthroline]2+ to DNA. The most stable binding geometry for both enantiomers is one in which a phenanthroline chelate is positioned in the major groove. The chelate is partially inserted between neighbouring base pairs, but is not intercalated. For delta, though not for lambda, a geometry with two chelates in the major groove is only slightly less favourable. Minor groove binding is shown to be no more favourable than external electrostatic binding. The optimised geometries of the DNA/[Ru(1,10-phenanthroline]2+ complexes enable published linear dichroism spectra to be used to determine the percentage of each enantiomer in the two most favourable major groove sites. For delta 57 +/- 15% and for lambda 82 +/- 7% of bound molecules are in the partially inserted site.

Base Sequence↗
PubMed1977

X-ray investigation of the binding of 1,10-phenanthroline and imidazole to horse-liver alcohol dehydrogenase.

We have studied the binding of two inhibitor molecules, imidazole and 1,10-phenanthroline, to liver alcohol dehydrogenase by crystallographic methods. X-ray data for the imidazole complex were collected to 0.29-nm resolution and for the 1,10-phenanthroline complex to 0.45-nm resolution. In both cases we found only one peak in the difference electron density maps close to the active zinc atom. The peak corresponding to 1,10-phenanthroline overlaps the site of the density of the zinc-bound water in the apoenzyme and the imidazole density partly overlaps this density. We can not discern any additional peaks close to the zinc atom which would correspond to new positions of bound water. We thus conclude that both these inhibitors bind to the catalytic zinc atom and that upon binding they displace the water molecule that is firmly bound to this zinc atom in the apoenzyme. We do not see any structural changes in the remaining part of the molecule.

Alcohol Oxidoreductases↗
PubMed1991

Differential protective effects of O-phenanthroline and catalase on H2O2-induced DNA damage and inhibition of protein synthesis in endothelial cells.

The respective roles of H2O2 and .OH radicals was assessed from the protective effects of catalase and the iron chelator o-phenanthroline on 1) the inhibition of protein synthesis, and 2) DNA damage and the related events (activation of the DNA repairing enzyme poly(ADP)ribose polymerase with the associated depletion of NAD and ATP stores) in cultured endothelial cells exposed to the enzyme reaction hypoxanthine-xanthine oxidase (HX-XO) or pure H2O2. Catalase added in the extracellular phase completely prevented all of these oxidant-induced changes. O-phenanthroline afforded a complete protective effect against DNA strand breakage and the associated activation of the enzyme poly(ADP)ribose polymerase. By contrast, iron chelation was only partially effective in maintaining the cellular NAD and ATP contents, as well as the protein synthetic activity. In addition, the ATP depletion following oxidant injury was much more profound than NAD depletion. These results indicate that: 1) .OH radical was most likely the ultimate O2 species responsible for DNA damage and activation of poly(ADP)ribose polymerase; 2) both H2O2 and .OH radicals were involved in the other cytotoxic effects (inhibition of protein synthesis and reduction of NAD and ATP stores); and 3) NAD and ATP depletion did not result solely from activation of poly(ADP)ribose polymerase, but other mechanisms are likely to be involved. These observations are also compatible with the existence of a compartmentalized intracellular iron pool.

Adenosine Triphosphate↗
PubMed1975

Enhancement of carrageenin foot oedema by 1,10 -phenanthroline and evidence for the bradykinin as endogenous mediator.

Carrageenin oedema in enhanced by the simultaneous injection in the rat paw of 1,10-phenanthroline, a kininase inhibitor. The analysis of the time-course of this enhancement showed that the maximal effect was observed about 3 hours after the injection. This enhancement was also present when the oedema-producing agent was cellulose sulphate, a kinin-releasing compound. On the contrary, oedema induced by eggwhite as well as by dextran, which are mainly mediated by histamine and 5-hydroxytryptamine, were unaffected by 1,10-phenanthroline. These results further support the role of kinins in the pathogenesis of carrageenin oedema.

Animals↗
PubMed1992

Chelatable metal ions are not required for aryl hydrocarbon receptor transformation to a DNA binding form: phenanthrolines are possible competitive antagonists of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The aryl hydrocarbon receptor (AhR) mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds by binding DNA and altering gene transcription. We determined whether AhR transformation to a DNA binding form requires chelatable metal ions. The chelator 1,10-phenanthroline and its nonchelating isomers 1,7- and 4,7-phenanthroline blocked, in a concentration-dependent manner, TCDD-elicited transformation of the AhR in rat hepatic cytosol to a form which bound a dioxin-response element (DRE; upstream of the structural gene for cytochrome P4501A1). This was found to be due to the ability of these compounds to competitively inhibit [3H]TCDD specific binding to the AhR under conditions in vitro. EDTA (20 mM) failed to inhibit DRE binding of the transformed AhR, but pretreatment of cytosol with EDTA prior to transformation inhibited DRE binding up to 60%. However, removal of EDTA from the cytosol by gel filtration prior to incubation with TCDD resulted in the same DRE binding as filtered control cytosol without the added divalent metal ions. Both chelators, oxalic acid and iminodiacetic acid, failed to inhibit DRE binding when added prior to AhR transformation. Together these data indicate that chelatable metal ions are not required for AhR transformation to the DNA binding form.

Animals↗
PubMed1975

The effect of o-phenanthroline on the midpoint potential of the primary electron acceptor of photosystem II.

The primary electron acceptor of Photosystem II has a midpoint oxidation-reduction potential of +95 mV at pH 7.0 in Photosystem II chloroplast fragments prepared by digitonin treatment. The midpoint potential of the acceptor has a pH dependence of -60 mV/pH unit. At concentrations that inhibit oxygen evolution, o-phenanthroline shifts the midpoint potential of the primary acceptor by +70 mV. The shifted potential retains the same dependence on pH. The effect of o-phenanthroline suggests that it interacts directly with the primary electron acceptor of photosystem II in a manner similar to that reported previously for the primary electron acceptor in purple photosynthetic bacteria.

Chloroplasts↗
PubMed1991

Inhibition of bleomycin-induced cellular DNA strand scission by 1,10-phenanthroline.

Inhibition by 1,10-phenanthroline of cellular DNA strand scission induced by the antitumor antibiotic bleomycin in Ehrlich ascites tumor cells was studied. DNA alkaline elution was performed on cells after 1-hr bleomycin treatments. Pretreatment for 24 hr with initial 1,10-phenanthroline concentrations of 0.2 nmol/10(5) cells, which depletes cells of ferritin iron by 80%, had no consistent effect on bleomycin strand breakage. However, simultaneous treatment with 3.1 nmol of 1,10-phenanthroline/10(5) cells and with bleomycin concentrations from 5 to 25 microM decreased both apparent double-stranded breaks and random breakage. When cells were treated with both 3.1 nmol of 1,10-phenanthroline/10(5) cells and 25 microM bleomycin, washed free of both drugs, and incubated at 35 degrees for 1 hr, the resulting breakage was equivalent to that found in cells treated with bleomycin only. When the combination treatment was extended to 4 hr, cell washing and reincubation resulted in increased strand scission, as compared with strand scission in cells treated with bleomycin only. Growth inhibition by bleomycin was not affected appreciably by temporary suppression of DNA strand breakage activity.

Animals↗
PubMed1978

Comparative actions of 1,10-phenanthroline nickel(II) chelates and their constituent metal ion and ligands on the guinea-pig isolated atrium.

The actions of fully co-ordinated, inert nickel(II) chelates of 1,10-phenanthroline and 3,4,7,8-tetramethyl-1,10-phenanthroline have been compared on the guinea-pig isolated atrium with those of their constituent metal ion and ligands. In general, each test substance showed distinctive actions suggesting that the effects of the metal chelates are mediated by the intact chelate cation and not by liberated metal ion or ligand. Differences in the actions of the unsubstituted and the highly methylated compounds may result from the greater capacity of the methylated chelate and ligand to induce more profound and sustained conformational changes in the responsive atrial pre- and postsynaptic membranes thereby promoting more rapid and prolonged influx of Ca2+.

Animals↗
PubMed1978

The inhibition of cyclo-oxygenase of rabbit platelets by aspirin is prevented by salicylic acid and by phenanthrolines.

Salicylic acid, 1,10- and 1,7-phenanthroline prevented inhibition by aspirin of platelet aggregation and of generation of thromboxane A2 due to arachidonic acid, to the ionophore A21387, to thrombin and to collagen. Dithiothreitol, another drug which prevents aggregation and formation of thromboxane A2, but only reversibly, failed to interfere with the inhibition by aspirin. Irreversible inhibition by indomethacin and by the substrate analogue 5,8,11,14-tetraynoic acid was also unaffected by salicylic acid or by 1,10-phenanthroline, which thus probably exert a specific interaction with the aspirin-binding site. Inactivation of platelet cyclo-oxygenase with arachidonic acid led to inhibition of the formation of thromboxane A2 and of aggregation due to arachidonic acid itself and to collagen, but barely affected aggregation by thrombin, even though generation of thromboxane A2 was blocked. Use of salicylic acid and of reversible inhibitors of cyclo-oxygenase may help to unravel the mechanism of inhibition due to other agents.

Animals↗