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PubMed2006

Determination of polyamines by flow injection analysis with a chemiluminescence detector based on their complexation with copper(II).

Through the flow injection analysis experiments, we discovered that an unsaturated complex of Cu(II) and polyamines (spermine, spermidine, putrescine) had a strongly catalytic effect on luminol-H(2)O(2) chemiluminescence (CL) reaction, and that the CL intensity is proportional to the concentrations of polyamines. Based on the automatic formation of an unsaturated complex of polyamines and Cu(II) when the solution containing polyamines passed through a column packed with solid Cu(OH)(2), a new flow injection chemiluminescence analysis method was proposed for the determination of polyamines. The effects of pH, buffer concentration, the concentration of chemiluminescence reagent, and the influence of mixing coil length were examined. Under optimal conditions, the linear range was from 1.0 x 10(-7) mol L(-1) to 1.0 x 10(-5) mol L(-1), and the detection limits were 0.17, 0.38, 0.44 pmol for spermine, spermidine, and putrescine, respectively. Compared with other methods, the advantages of this method include convenience, time-saving and low cost.

Biogenic Polyamines↗
PubMed2005

Competition of natural polyamines with dimethylsilyl analogues and monovalent cations in presence of a charged dipalmitoylphosphatidylglycerol monolayer.

The interaction at the air/water interface of dipalmitoylphosphatidylglycerol (DPPG) with natural and dimethylsilyl polyamines are investigated first in the presence of NaCl in the subphase. Next, experiments are performed to study the competition between natural polyamines and dimethylsilyl analogues. The results obtained by surface pressure and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) with NaCl, are compared with those obtained with distilled water. A decrease of the DPPG mean molecular area is observed due to the local diminution of the Na+ concentration close to the polar head group and the simultaneous onset of interactions between the amino group of natural polyamines and the polar head group of DPPG. The same effects occur with azhepsi, followed by an insertion of the hydrophobic dimethylsilyl group. Near the polar head groups DPPG, a substitution of the Na+ by the amino groups of polyamines occurs. For the competition experiments, whereas a partial substitution is possible after putrescine and spermine adsorption, it is almost complete after spermine adsorption. Since the number of amino groups of azhepsi and spermine are the same, hydrophobic interactions due to the presence of dimethylsilyl group occur between azhepsi and the alkyl chains of DPPG. This favoured insertion of azhepsi provides a basis for understanding of the action of dimethylsilyl derivatives in the case of an antitumour strategy.

Adsorption↗
PubMed1989

Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells.

The effects on methionine metabolism of the substitution of homocysteine for methionine in vitro were investigated in normal and tumor cell lines differing in their ability to utilize homocysteine for growth. The major finding of this study was that methionine-independent (Met-Indep) cell lines had much lower basal transmethylation rates than methionine-dependent (Met-Dep) cell lines. This was particularly evident in the parent SP1 cell line and its Met-Indep revertant, SP1-R. SP1-R compensated for a lack of methionine by reducing both its transmethylation and growth rates. An analysis of other potential differences in methionine metabolism between Met-Dep and Met-Indep cell lines failed to demonstrate any consistent abnormalities in all but the absolutely Met-Dep MDAY-D2 cell line. Thus, protein, S-adenosylmethionine, and polyamine synthesis were the same in Met-Dep and Met-Indep cell lines. These results indicate that the major regulatory step in determining the Met-Dep phenotype is an inherent increase in the rate of transmethylation reactions. Cell lines with high basal transmethylation rates cannot compensate for a relative deficiency of methionine and either cease growing (MDAY-D2) or generate revertants (SP1-R) for which the basal rate of transmethylation is considerably reduced.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1991

Evaluation of the antimicrobial activity of methylglyoxal bis(guanylhydrazone) analogues, the inhibitors for polyamine biosynthetic pathway.

Metabolic and antiproliferative effects of methylglyoxal bis(butylamidinohydrazone) (MGBB) and methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), inhibitors for polyamine biosynthetic pathway, on Escherichia coli, Shigella sonnei, Aeromonas sobria, Aeromonas hydrophila and Vibrio cholerae were investigated. MGBB at the concentration of 100 mumol/l depleted intracellular putrescine and spermidine concentrations of E. coli to 25 and 20% of the controls, respectively, while MGBCP depressed their concentrations to 38 and 24%, respectively. In these polyamine-depleted E. coli cells the syntheses of RNA, DNA and protein decreased to 13, 54 and 29% of the control, respectively, with MGBB and to 23, 71 and 55%, respectively, with MGBCP. The minimum inhibitory concentrations (MIC) of MGBB for the growth of A. sobria, E. coli, A. hydrophila, V. cholerae and Sh. sonnei were estimated to be 50, 160, 240, 285 and 320 mumol/l, respectively, whereas those of MGBCP were slightly higher for respective bacteria.

Bacteria↗
PubMed1994

Induction of low-affinity GABAA receptors by the GABA-agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cultured rat cerebellar granule cells is prevented by inhibition of polyamine biosynthesis.

GABAA agonist-induced formation of low-affinity GABAA receptors in cultured cerebellar granule cells was studied in the presence or absence of alpha-difluoromethylornithine (DFMO), a blocker of polyamine formation. High- and low-affinity GABAA receptors were monitored by Scatchard analysis of [3H]GABA binding to membranes from cells cultured for either 4 or 10 days in the presence or absence of the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Cultures grown for 4 days were exposed to THIP and DFMO for an additional period of 6 hr (acute exposure), whereas cultures grown for 10 days were exposed to the same agents during the entire culture period (chronic exposure). Regardless of the culture period or drug exposure protocol, control cells expressed only a high-affinity (KD 7 nM) binding site for GABA, whereas the cultures treated with THIP for either 6 hr or 10 days exhibited an additional low-affinity binding site (KD approximately 500 nM). Chronic exposure to DFMO prevented the THIP induction of low-affinity GABAA receptors, whereas acute exposure to DFMO had no effect on the ability of THIP to induce low-affinity GABAA receptors. Measurements of the intracellular polyamine concentration demonstrated a slight decrease in the putrescine level in the granule cells exposed to DFMO or THIP + DFMO for 6 hr. In contrast, granule cells chronically (10 days) exposed to DFMO or THIP + DFMO were depleted of putrescine and spermidine. Hence, the ability of THIP to induce low-affinity GABAA receptors was prevented by the simultaneous depletion of the cellular content of putrescine and spermidine, whereas inhibition of ornithine decarboxylase and of putrescine formation was not sufficient to prevent THIP-induced receptor formation.

Animals↗
PubMed2000

Different effects of acute neonatal stressors and long-term postnatal handling on stress-induced changes in behavior and in ornithine decarboxylase activity of adult rats.

A transient increase in brain polyamine (PA) metabolism, termed the PA-stress-response (PSR), is a common response to stressful stimuli. Previous studies have implicated the PSR as a component of the adaptive and/or maladaptive brain response to stressful events. Ample evidence indicates that stressful experiences during early life can alter normal developmental processes and may result in pathophysiological and behavioral changes in the adult. The aim of the present study, therefore, was to determine whether strong acute neonatal stressors (3 mg/kg dexamethasone, or 2 h restraint stress at day 7), as compared to mild long-term intermittent maternal separation and handling (15 min, twice a day between postnatal days 2 and 25), would lead in adult Wistar rats to different PSR and behavioral reactivity to novelty stress. Changes in ornithine decarboxylase (ODC) activity and in tissue PA concentrations served as markers of the PSR, and behavioral alterations in an open-field arena indicated the reactivity to novelty stress. Animals subjected to acute neonatal stressors, showed reduced behavioral reactivity in the open-field test, indicative of increased emotional reactivity to novelty. In these animals, the increase in ODC activity after dexamethasone challenge was attenuated in the brain, but exaggerated in the liver. In the thymus and adrenal gland of these animals, the basal enzyme activity was significantly increased, but a similar reduction was observed after dexamethasone challenge. In contrast, long-term postnatal handling led in adults to novelty-induced changes indicative of reduced emotional behavior, yet the alterations in ODC activity after dexamethasone challenge in these animals were similar to those in animals after acute stressors. The concentrations of tissue polyamines in adults were not affected by any of the postnatal stressors. The results justify the following conclusions: (1) Strong acute neonatal stressors can lead to increased emotional behavior in adults, while mild long-term intermittent handling, may result in adaptation and reduced emotionality. (2) Attenuated stress-induced increase of ODC activity in the brain, but exaggerated increased activity in the liver, may be implicated in altered emotional behavior reactivity to stressors.

Acute Disease↗
PubMedDate not supplied

Synergistic activation of macrophage activity by polyamine deprivation and cyclophosphamide.

A synergistic reduction in tumor growth rate and of metastasis dissemination together with an increased life span, were observed when polyamine deprivation was combined with a low dose of cyclophosphamide. When rats were treated with this combination treatment, TNF and NO release was enhanced and phagocytic activity was increased. In addition, PGE2 release by macrophages was enhanced, whereas PGE2 plasma levels were restored to normal values. The decrease in PGE2 plasma levels presumably indicates the synergistic effect of the combination treatment on tumor cell metabolism. The enhancement of macrophage tumoricidal activities indicates immunostimulating synergistic effects, which may contribute to the anti-tumoral effect of the treatment.

Animals↗
PubMed1998

Polyamine modulation of mitochondrial calcium transport. II. Inhibition of mitochondrial permeability transition by aliphatic polyamines but not by aminoglucosides.

In this study, the effects of polyamines and analogous compounds on mitochondrial permeability transition were characterized to distinguish between these effects and those on mitochondrial Ca2+ uptake, which are described in an accompanying report (Rustenbeck et al., Biochem Pharmacol 8: 977-985, 1998). When a transitional Ca2+ release from Ca2+-loaded mitochondria was induced by an acute increase in Ca2+ concentration in a cytosol-adapted incubation medium (Ca2+ pulse), this process was inhibited, but not abolished by spermine in the concentration range of 0.4 to 20 mM. The aminoglucoside, gentamicin, and the basic polypeptide, poly-L-lysine, which like spermine are able to enhance mitochondrial Ca2+ accumulation (preceding paper), had no or only a minimal inhibitory effect, while the aliphatic polyamine, bis(hexamethylene)triamine, which is unable to enhance mitochondrial Ca2+ accumulation, achieved a complete inhibition at 4 mM. The conclusion that the Ca2+ efflux was due to opening of the permeability transition pore was supported by measurements of mitochondrial membrane potential, ATP production, and oxygen consumption. Mg2+, a known inhibitor of mitochondrial membrane permeability transition, did not mimic the effects of spermine on mitochondrial Ca2+ accumulation, while ADP, the main endogenous inhibitor, showed both effects. However, a combination of spermine and ADP was significantly more effective than ADP alone in restoring low Ca2+ concentrations after a Ca2+ pulse. Two different groups of spermine binding sites were found at intact liver mitochondria, characterized by dissociation constants of 0.5 or 4.7 mM and maximal binding capacities of 4.6 or 19.7 nmol/mg of protein, respectively. In contrast to aminoglucosides, the aliphatic polyamine bis(hexamethylene)triamine did not displace spermine from mitochondrial binding sites. The total intracellular concentration of spermine in hepatocytes was measured to be ca. 450 microM and the free cytoplasmic concentration was estimated to be in the range of 10-100 microM. In conclusion, the enhancement of mitochondrial Ca2+ uptake by spermine is not an epiphenomenon of the inhibition of permeability transition. The physiological role of spermine appears to be that of an enhancer of mitochondrial Ca2+ accumulation rather than an inhibitor of permeability transition.

Aminoglycosides↗
PubMed2006

The new orally active iron chelator ICL670A exhibits a higher antiproliferative effect in human hepatocyte cultures than O-trensox.

By comparing the antiproliferative effect of the iron chelators ICL670A and O-trensox in the human hepatoma cell line HUH7 and human hepatocyte cultures, we have shown that ICL670A decreased cell viability, inhibited DNA replication and induced DNA fragmentation more efficiently than O-trensox. O-trensox and ICL670A induced a cell cycle blockade in G0-G1 and S phases respectively. In parallel, ICL670A inhibited polyamine biosynthesis by decreasing ornithine decarboxylase and spermidine/spermine N(1)-acetyltransferase activities. O-trensox increased polyamine biosynthesis and particularly putrescine level by stimulating spermidine-spermine N(1)-acetyltransferase activity which could activate the polyamine retro-conversion pathway. Moreover, the two chelators exhibit some cytotoxic effect in the two culture models; ICL670A was more cytotoxic than O-trensox and higher concentrations of the two chelators were necessary to induce a cytotoxicity in primary cultures versus hepatoma cells. These results suggested that ICL670A has the most efficient antitumoral effect, blocks cell proliferation by a pathway different of O-trensox and may constitute a potential drug for anticancer therapy.

Acetyltransferases↗
PubMed1998

Long-term effects of status epilepticus induced by kainic acid on hippocampal polyamines.

Putrescine has been suggested to have an inhibitory effect on the excitability of the central nervous system. In the present study we found that 2 and 3 weeks after status epilepticus induced by kainic acid, rats had increased concentrations of putrescine (3- and 1.7-fold, respectively) and spermidine (1.6- and 1.4-fold, respectively) in the hippocampus. These animals exhibited a higher susceptibility to pentylentetrazol than the saline group. In addition, several hours after the pentylentetrazol injection, the concentration of putrescine and spermidine increased again in the brain and also in the plasma. In conclusion, increased hippocampal putrescine and spermidine concentrations seem to be linked with a lower threshold of excitability.

Animals↗
PubMed2006

The polyamine binding site in inward rectifier K+ channels.

Strongly inwardly rectifying potassium channels exhibit potent and steeply voltage-dependent block by intracellular polyamines. To locate the polyamine binding site, we have examined the effects of polyamine blockade on the rate of MTSEA modification of cysteine residues strategically substituted in the pore of a strongly rectifying Kir channel (Kir6.2[N160D]). Spermine only protected cysteines substituted at a deep location in the pore, between the "rectification controller" residue (N160D in Kir6.2, D172 in Kir2.1) and the selectivity filter, against MTSEA modification. In contrast, blockade with a longer synthetic polyamine (CGC-11179) also protected cysteines substituted at sites closer to the cytoplasmic entrance of the channel. Modification of a cysteine at the entrance to the inner cavity (169C) was unaffected by either spermine or CGC-11179, and spermine was clearly "locked" into the inner cavity (i.e., exhibited a dramatically slower exit rate) following modification of this residue. These data provide physical constraints on the spermine binding site, demonstrating that spermine stably binds at a deep site beyond the "rectification controller" residue, near the extracellular entrance to the channel.

Animals↗
PubMed1994

Expression of a human S-adenosylmethionine decarboxylase cDNA in transgenic tobacco and its effects on polyamine biosynthesis.

S-adenosylmethionine decarboxylase (SAMDC; EC 4.1.1.50) is a key regulatory enzyme in the polyamine biosynthetic pathway. Numerous studies have shown that the enzyme activity and polyamine levels are generally correlated with cellular growth in plants, animals and bacteria. In order to gain more insight into the role of polyamines in plants, human SAMDC cDNA under control of 35S promoter of cauliflower mosaic virus, along with a neomycin phosphotransferase gene, was transferred to tobacco (Nicotiana tabacum cv.Xanthi) via Agrobacterium tumefaciens. Transgenic plants showed the presence of SAMDC mRNA and a 2-4-fold increase in SAMDC activity. In the transformed tissues, putrescine levels were significantly reduced, while spermidine content was 2-3 times higher than the control tissues. Cellular spermine content was either increased or remained unchanged. Excised leaf segments from transformed plants frequently produced shoots even on callus inducing medium.

Adenosylmethionine Decarboxylase↗
PubMed1990

Dissimilar trophic effects of cerulein and xenopsin on the rat pancreas.

Cholecystokinin (CCK), gastrin, cerulein, and other analogs are known to stimulate the growth of the rat pancreas. In the present study, we compared the trophic action of a member of this gastrin/CCK family, the amphibian peptide cerulein, with a member of the structurally unrelated neurotensin/xenopsin group, the amphibian peptide xenopsin. For this purpose, 0.56 nmols/kg cerulein, 1.0 nmols/kg xenopsin, or normal saline were injected intraperitoneally three times a day in 28 rats for 3 d. Pancreatic weight, DNA, and incorporation of 3H-thymidine into DNA were determined. In another study, pancreatic weight, DNA, and the polyamines, putrescine, spermidine, and spermine, were determined after a single dose of 2.7 nmol/kg cerulein, 4.5 nmol/kg xenopsin, or saline. The polyamines were measured by reverse-phase HPLC and post-column derivatization. Cerulein increased pancreatic weight, stimulated 3H-thymidine incorporation into DNA, and raised putrescine concentrations significantly, but led to a significant reduction of pancreatic DNA concentration. Xenopsin also stimulated 3H-thymidine incorporation into DNA, but did not affect pancreatic weight, DNA concentration, or the polyamines during the 4 h of the experiment. These findings suggest that cerulein, in the dose and intervals applied, initiated hyperplasia and induced hypertrophy of the pancreas, whereas xenopsin only initiated hyperplasia. These results, together with the dissimilar secretory effects of the two peptide families, may be the expression of a dissimilar mode of action. However, it cannot be excluded that, since cerulein is more potent than xenopsin, the differences also are owing to dosage. We conclude that cerulein and xenopsin, which both have trophic effects on the pancreas, may act by different mechanisms.

Animals↗
PubMed1994

Osteopontin: its transglutaminase-catalyzed posttranslational modifications and cross-linking to fibronectin.

Osteopontin (OP) is a component of extracellular, bone, and urinary stone matrices, but the mechanism by which it is stably incorporated into such matrices remains unknown. By SDS-PAGE analysis of [125I]OP, treated with a catalytic amount of TG, we first demonstrate both intra- and intermolecular covalent cross-linking of OP. Most importantly, the analysis of the products generated from reactions containing OP, Fn, and TG by SDS-PAGE, autoradiography, and Western blotting using either OP or Fn antibody, and quantitation of TG-catalyzed epsilon-(gamma-glutamyl)lysine isopeptide formation between OP and Fn demonstrate, for the first time, covalent cross-linking between these two proteins. Similar reactions in the presence of polyamine substrates of TG show OP-Fn intermolecular cross-linking via N,N-bis-(gamma-glutamyl)polyamine formation. Finally, immunoprecipitation of 125I-labeled NRK cell surface proteins with anti-OP and anti-Fn antibodies, SDS-PAGE analysis, and autoradiography provides critical evidence for nonreducible OP-Fn cross-linking in vivo. These results clearly suggest that TG-mediated cross-linking between OP and Fn represents one of the most likely mechanisms by which OP becomes covalently linked to bone matrix, urinary stone matrix, and to ECM.

Amino Acid Sequence↗
PubMed1989

Simple, sensitive assay of polyamines by high-performance liquid chromatography with electrochemical detection after post-column reaction with immobilized polyamine oxidase.

This simple, rapid liquid-chromatographic assay of urinary polyamines (putrescine, spermidine, spermine, and cadaverine) involves electrochemical detection with a post-column immobilized enzyme, polyamine oxidase (EC 1.4.3.6) from soybean seedlings. Polyamines are separated by isocratic ion-pairing reversed-phase chromatography, then enzymatically converted, with release of hydrogen peroxide, via the post-column reactor with immobilized polyamine oxidase; the hydrogen peroxide is detected by electrochemical oxidation on a platinum electrode. The detection limits for injected putrescine, spermidine, and spermine were 0.3, 0.5, 0.6, and 4 pmol, respectively, with linear ranges of two to three orders of magnitude. Reproducibility was also good, with CV values less than 7%. The efficiency of the immobilized enzyme column was not decreased after analysis of 300 urine samples. Putrescine and spermidine excretion in urine from patients with blood cancers and solid cancers was significantly increased.

Biogenic Polyamines↗
PubMed1990

Regulation of diamine oxidase expression by ornithine decarboxylase in isolated rat small bowel enterocytes.

Ornithine decarboxylase (ODC) and diamine oxidase (DAO), enzymes involved in polyamine metabolism, are highly expressed by small bowel enterocytes. Modulation of ODC expression is mediated through cellular concentration of polyamines that inhibits the enzyme synthesis and also induces the synthesis of an inhibitory protein, the antizyme, which in turn binds to ODC and inhibits its activity. DAO is an important regulator of intracellular concentration of polyamines because it catalyzes the degradation of putrescine into gamma-aminobutyraldehyde. Change in intracellular polyamine concentration has been suggested to represent a regulatory factor for DAO expression. In order to investigate a possible regulation of DAO expression by ODC, we studied the effect of difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ODC, on DAO activity in isolated rat small bowel enterocytes. Our data demonstrate that in isolated small bowel enterocytes ODC inhibition by 10 mM DFMO reduced DAO activity by 53%, suggesting that, in our experimental conditions, ODC plays a regulatory role on DAO expression.

Amine Oxidase (Copper-Containing)↗
PubMed1998

Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia.

alpha-Difluoromethylornithine (DFMO) is a suicide inhibitor of ornithine decarboxylase and potent antiproliferative chemopreventive agent. We conducted a dose de-escalation Phase I trial of DFMO in patients with grade 3 cervical intraepithelial neoplasia to determine an optimal dose of DFMO using ornithine decarboxylase activity and polyamine modulation as surrogate biomarkers and to evaluate its toxicity. Thirty patients with biopsy-confirmed grade 3 cervical intraepithelial neoplasia were assigned sequentially to one of five DFMO doses (1.000, 0.500, 0.250, 0.125, or 0.060 g/m2) given daily for 31 days. One patient was excluded from analysis for protocol violation. Polyamine levels were assessed in cervical tissue, plasma, and RBCs. Tissue and blood samples were obtained before and after treatment with DFMO. All patients underwent loop excision of the cervix at the end of the study for complete histological evaluation and definitive treatment of the premalignant condition. No major clinical toxicity was observed at any DFMO dose. A reduction in tissue spermidine to spermine (SPD:SPM) ratio and an increase in plasma arginine levels were observed among patients receiving 1.000 g/m2/day (P < 0.05). A nonsignificant reduction in SPD:SPM ratio was also observed in the 0.500 g/m2/day dose group, and a nonsignificant increase in plasma arginine level was observed down to the 0.125 g/m2/day dose level. There was no evidence of modulation of other polyamines or precursors. Fifteen patients experienced a complete (5 patients) or partial (10 patients) histological response. In conclusion, DFMO was well tolerated and significantly modulated tissue SPD:SPM ratio and plasma arginine level at the dose of 1.000 g/m2/day. To clarify whether DFMO has activity at lower doses, these results will be tested in a three-armed double-blinded Phase II study using placebo and DFMO doses of 0.500 and 0.125 g/m2/day.

Administration, Oral↗
PubMed2001

Oxidation products of polyamines induce mitochondrial uncoupling and cytochrome c release.

Spermine is shown to uncouple isolated mitochondria and to trigger the selective release of cytochrome c. Pargyline, an inhibitor of amine oxidase (AO), fully prevented these effects of spermine, which instead were potentiated by exogenous AO. Hydrogen peroxide, an oxidation product of spermine, mimicked the effects of spermine on mitochondria, while the addition of catalase prevented them. Spermidine and putrescine also caused mitochondrial uncoupling and triggered cytochrome c release, with a potency which correlated with the substrate preference of mitochondrial AO. Pargyline protected human lymphoma U937 cells against UVB-induced apoptosis, by reducing AO activity, mitochondrial uncoupling and cytochrome c release.

Amine Oxidase (Copper-Containing)↗