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PubMed1986

Identification of polyamines in the cochlea of the rat and their potential role in hearing.

The occurrence of reversible hearing loss in patients treated with the polyamine biosynthesis inhibitor, alpha-difluoromethylornithine (DFMO), led to the hypothesis that this functional hearing deficit might be due to polyamine depletion in the cochlea. To test this hypothesis the polyamine content (putrescine, spermidine and spermine) of the cochleas of normal rats was measured and compared to that of DFMO-treated rats. For the first time, it was demonstrated that in the cochleas of normal rats there were substantial amounts of spermidine and spermine but no detectable putrescine. There was also no measurable ornithine decarboxylase. The DFMO treatments employed in this study were not effective, however, in depleting the cochlear polyamines to levels generally considered critical for disrupting polyamine-dependent processes in other systems. Thus, it is not surprising that auditory thresholds, which were evaluated using brainstem evoked potentials, remained unaltered in the DFMO-treated rats. Demonstration of a role for polyamines in hearing awaits further investigation with the use of more potent inhibitors or other model systems for hearing.

Animals↗
PubMed1990

Regulation of polyamine biosynthesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

We have examined the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on tissue polyamine concentrations in CD1 mice. Two days after a low dose treatment with TCDD, polyamine content of the liver and thymus of treated mice showed a 49-82% decrease, but that of spleen was not affected. Based on this finding, we examined the role of alterations in polyamine levels in the toxicity of TCDD. We administered the polyamine biosynthetic inhibitor difluoromethylornithine (DFMO) to animals treated with a toxic dose of TCDD. DFMO dramatically increased the toxicity of TCDD as measured by mortality, ascites and changes in organ weights. In addition, administration of the polyamine putrescine was able to reduce the toxicity of TCDD. These results suggest that a decrease in polyamine concentrations in critical organs may play an important role in the toxic effects of TCDD.

Animals↗
PubMed1995

Investigation of polyamine metabolism by high-performance liquid chromatographic and gas chromatographic profiling methods.

Measurements of polyamines, polyamine conjugates and their metabolites in tissues, cells and extracellular fluids are used in biochemistry, (micro)biology, oncology and parasitology. Decarboxylation of ornithine yields putrescine. Aminopropylation of putrescine yields spermidine, and aminopropylation of spermidine yields spermine. Spermidine and spermine are retroconverted to putrescine and spermidine, respectively, by initial N-acetylation and subsequent polyamine oxidation. The intermediate N-acetylputrescine, N1-acetylspermidine and N8-acetylspermidine are the major urinary N-acetylpolyamines. Polyamines and N-acetylpolyamines are terminally degraded to non-alpha-amino acid metabolites by oxidative deamination and aldehyde dehydrogenation. Chromatography with on-line detection is the most commonly applied profiling method for polyamines, N-acetylpolyamines and their non-alpha-amino acid metabolites. Cation-exchange and reversed-phase high-performance liquid chromatography require pre- or post-column derivatisation, followed by UV-Vis spectrophotometric or fluorimetric detection. Isolation and derivatisation precedes gas chromatography with flame-ionisation, nitrogen-phosphorus, electron-capture or mass spectrometric detection. High-performance liquid chromatography and gas chromatography of polyamines are not competitive techniques, but rather supplementary.

Chromatography, Gas↗
PubMed1994

Postnatal changes in cochlear polyamine metabolism in the rat.

Ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway, is increased in the developing rat cochlea, suggesting that polyamine biosynthesis is important in cochlear development. Although cochlear polyamines have been detected in adult rats, they have not been identified in developing rats. We quantified polyamines in the developing and mature rat cochlea and further characterized ODC in the early postnatal period. Putrescine and spermidine in combined tissues of the organ of Corti and lateral wall of the cochlea were highest during the first 10 postnatal days, then declined to adult levels shortly thereafter. Spermine demonstrated a similar developmental trend. A high spermidine to spermine ratio was noted during this period as was rapidly increasing ODC activity. A high spermidine/spermine ratio was also noted in the cochlear nerve of developing and mature rats, suggesting that spermidine may be necessary for function and maintenance of the nerve. This is the first report of polyamines in the developing rat cochlea. The period of increased polyamine synthesis coincides with the critical period for ototoxicity induced by alpha-difluoromethylornithine, a specific ODC inhibitor, and the period of rapid cochlear development.

Analysis of Variance↗
PubMed1990

Aging and intestinal polyamine metabolism in the rat.

Hyperproliferation and delayed expression of enzyme activity occur in small intestinal enterocytes of aging rats, and starvation and refeeding result in impaired control of these processes. Since altered polyamine metabolism may accompany changes in enterocyte proliferation, we studied the effects of nutrient manipulation upon cell numbers, ornithine decarboxylase (ODC) activity and polyamine content in jejunum and ileum of 4- to 5- and 26- to 27-month Fischer rats. In both groups, cell numbers fell during starvation and and increased during refeeding. Crypt cell hyperplasia was found in aging animals. Jejunal putrescine, spermine and spermidine content were greater in older rats, fell during starvation, and rose during refeeding. Ileal ODC activity was 66% greater in the aging rats, but jejunal ODC activity was modestly increased in young animals. Intestinal polyamine content correlates with proliferative changes and polyamine metabolism responds appropriately to nutrient manipulation during aging. Dissociation of ODC activity and polyamine content in aging jejunum probably occurred because enterocyte differentiation was delayed. Investigation of intestinal polyamine metabolism may be useful in elucidating deranged proliferative activities found in the intestine of aging rodents.

Age Factors↗
PubMed1991

Role of polyamine in the regulation of RNA synthesis in uterine nucleoli.

Administration of estradiol (E2) to ovariectomized mature rats has been shown to result in synthesis of uterine polyamines in the same temporal manner as E2 regulation of nucleolar transcription. Data is presented on the in vivo and in vitro effects of polyamines on uterine nucleolar RNA synthesis. Transcervical intrauterine administration of putrescine (100 micrograms), spermidine (100 micrograms), or spermine (100 micrograms) resulted in an increased transcriptional activity of 93 and 82% in uterine nucleoli isolated from putrescine and spermidine treated animals, respectively. Spermine administration was without effect on uterine nucleolar transcription. The polyamine-induced increase in transcription was totally accounted for by an increased rate of elongation of previously initiated RNA chains. No effect on the number of nucleolar RNA chains in the act of synthesis was observed. Preincubation of uterine nucleoli, isolated from control animals (no E2) with putrescine, spermidine, or spermine in the presence, but not in the absence of ATP, resulted in 44, 83 and 31% increased nucleolar RNA synthesis, respectively. In vitro polyamine-induced nucleolar RNA synthesis was correlated with a polyamine activated phosphorylation of nucleolar proteins of 110,000 24,000, 18,000 and 14,000 Da. Results suggest that early E2 action may result in activation of the polyamine pathway which modulates nucleolar protein kinase activity; initiating an increase in nucleolar transcription.

Adenosine Triphosphate↗
PubMed2005

Simultaneous determination of free and N-acetylated polyamines in urine by semimicro high-performance liquid chromatography using 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride as a fluorescent labeling reagent.

We have developed a simple and highly sensitive semimicro high-performance liquid chromatographic method for the simultaneous determination of free and N-acetylated polyamines in urine. Polyamines and N-acetylated polyamines were derivatized with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride to produce fluorescent sulfonamides. The labeling reaction was carried out at 50 degrees C for 15 min at pH 9. The fluorescent derivatives were separated on a reversed-phase column with a gradient elution using water-acetonitrile-methanol at 50 degrees C and detected by fluorescence measurement at 318 nm (excitation) and 406 nm (emission). The detection limits (signal-to-noise ratio=3) of the polyamines and N-acetylated polyamines were 0.7-4.5 fmol/injection. The within-day and day-to-day relative standard deviations were 3.2-7.9 and 3.0-7.7%, respectively. Significant differences were found in the urinary excretion of polyamines between cancer patients and normal subjects.

Acetylation↗
PubMed2005

Polyamine sensing during antizyme mRNA programmed frameshifting.

A key regulator of cellular polyamine levels from yeasts to mammals is the protein antizyme. The antizyme gene consists of two overlapping reading frames with ORF2 in the +1 frame relative to ORF1. A programmed +1 ribosomal frameshift occurs at the last codon of ORF1 and results in the production of full-length antizyme protein. The efficiency of frameshifting is proportional to the concentration of polyamines, thus creating an autoregulatory circuit for controlling polyamine levels. The mRNA recoding signals for frameshifting include an element 5' and a pseudoknot 3' of the shift site. The present work illustrates that the ORF1 stop codon and the 5' element are critical for polyamine sensing, whereas the 3' pseudoknot acts to stimulate frameshifting in a polyamine independent manner. We also demonstrate that polyamines are required to stimulate stop codon readthrough at the MuLV redefinition site required for normal expression of the GagPol precursor protein.

Animals↗
PubMed2005

Pharmacological aspects of cytotoxic polyamine analogs and derivatives for cancer therapy.

During the past 20 years, numerous derivatives and analogues of spermidine (Spd) and spermine (Spm) were synthesized with the aim to generate a new type of anticancer drug. The common denominator of most cytotoxic polyamine analogues is their lipophilicity, which is superior to that of the parent amines. The natural polyamines bind to polyanions and to proteins with anionic binding sites. Their hydrophilicity/hydrophobicity is balanced, allowing them to perform physiological functions by interacting with some of these anionic structures, without impairing the functionality of others. Because the attachment of lipophilic substituents to the polyamine backbone increases the binding energy, lipophilic polyamine derivatives affect secondary and tertiary structures of a larger number of macromolecules than do their natural counterparts. In addition, lipophilicity improves the blood-brain barrier transport and thus enhances CNS toxicity. Close structural analogues of spermidine and spermine mimic the natural polyamines in regulatory functions. The cytotoxic mechanisms of analogues with a less close structural resemblance to spermidine or spermine have not been completely clarified. The displacement of spermidine from functional binding sites and the consequent prevention of its physiological roles is a likely mechanism, but many others may play a role as well. Up to now, polyamine analogues were conceived without specific growth-related targets in mind. To develop therapeutically useful drugs, it will be imperative to identify specific targets and to design compounds that interact selectively with the target molecules. It will also be necessary to include, at an early state of the work, pharmacological and toxicological considerations, to avoid unproductive directions.

Animals↗
PubMed1997

Disruption of polyamine modulation by a single amino acid substitution on the L3 loop of the OmpC porin channel.

Structural studies have demonstrated that the extracellular L3 loop of porin constricts the channel and suggest that this loop might be involved in channel selectivity and gating. We previously showed that positively charged polyamines can induce changes in porin gating kinetics by stabilization of closed states. Here we report the effects of the mutation of two different aspartate residues of Escherichia coli OmpC porin on the polyamine sensitivity of the channel. Aspartate 105 or aspartate 118 on the L3 loop was replaced by glutamine by site-directed mutagenesis. The gating activity of the wild-type and mutant channels were studied by patch-clamp of liposomes containing reconstituted outer membrane fractions, in the absence or the presence of either polyamine spermine or cadaverine. Porin channels with a D118Q mutation, at the root of L3, still showed some, albeit milder, sensitivity to polyamine modulation. On the other hand, the D105Q mutation, at the tip of L3, abolished the increase in closing frequency which is typically observed in the presence of polyamines. We conclude that aspartate 105 primarily, but not aspartate 118, plays an important role in mediating the polyamine-induced changes in gating kinetics that result in the inhibition of the OmpC channel.

Aspartic Acid↗
PubMed1991

Casein kinase II and polyamines may interact in the response of adrenocortical cells to their trophic hormone.

The ubiquitous casein kinase II (CKII) has been shown to accumulate in the cell nuclear compartment, following exposure to extracellular growth stimuli (O. Filhol et al., Biochemistry, 1990, 29, 9928-9936). The aim of the present study was to examine whether intracellular polyamines, whose levels are increased under similar conditions, could be related to this process. It is shown that (i) CKII accumulates in nuclei of adrenocortical cells exposed to their trophic hormone ACTH; (ii) this CKII nuclear translocation is concomitant with an increase in nuclear polyamine content resulting from ACTH-induced polyamine synthesis; (iii) selective inhibition of polyamine biosynthesis by DFMO results in the inhibition of both ACTH-induced cellular polyamine increase and CKII nuclear accumulation. These observations suggest that polyamines may be examined as intracellular messengers in the regulation of CKII activity and subcellular distribution in the cell response to growth factors and trophic hormones.

Adrenal Cortex↗
PubMed2002

Correlation between polyamines and apoptosis among Egyptian breast cancer patients.

OBJECTIVES: The polyamines putrescine, spermidine, and spermine, play an important role in cell proliferation, differentiation, and transformation. The aim of this study is to correlate the polyamines with apoptosis and clinico-pathologic events in Egyptian breast cancer patients. METHODS: PUT, SPD, and SPN were investigated using thin layer chromatography (TLC) and apoptosis in fresh frozen tissue specimens obtained from 40 patients suffering from breast cancer, as well as 20 patients with benign breast lesions. RESULTS: The levels of PUT, SPD, and SPN were higher in breast cancer tissues than in benign breast lesions (p < 0.001). Polyamines were correlated well with apoptosis. Moreover, PUT was an independent prognostic factor for relapse. Also, SPD and SPN correlated significantly with early tumor grades. ROC curves were used to choose the best cut-off values for polyamines (70, 135, and 290 mmol/g tissue) for PUT, SPD, and SPN, respectively. At these cut-off values, the sensitivities were (75%, 60%, and 70%), and the specificities were (80%, 95%, and 95%) for PUT, SPD, and SPN, respectively. CONCLUSION: Polyamines may be used as additional markers for detection of malignant transformation in breast tissue. Moreover, because of their ability to induce apoptosis in malignant tissues, polyamines are suitable targets for therapeutic intervention that is specifically directed to induce apoptosis.

Apoptosis↗
PubMed2003

Elevated levels of polyamines alter chromatin in murine skin and tumors without global changes in nucleosome acetylation.

Polyamines affect nucleosome oligomerization and DNA conformation in vitro, yet little information exists regarding the influence of naturally synthesized polyamines on mammalian chromatin. Capitalizing on the relative inefficiency of a moderate ionic strength extraction buffer to dissociate histones, we obtained evidence of altered chromatin in transgenic mice that overexpress ornithine decarboxylase (ODC), which catalyzes polyamine synthesis. Dissociation of histones from chromatin in ODC transgenic mouse skin, as well as in tumors that develop spontaneously in ODC/Ras bigenic mice, is dramatically reduced relative to normal littermate skin. This could reflect tighter tethering of nucleosomes to DNA or a more compacted chromatin structure due to elevated intracellular concentrations of polyamines since this effect is reversible upon treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC enzymatic activity. Impeded release of nonhistone chromatin proteins HP-1beta and nucleophosmin, but not Lamin B, HDAC-1, HMGB, HMGN2, or HMGA1, suggests that polyamines exert selective effects on specific chromatin protein complexes. Moreover, overall acetylation, as well as specific methylation, of nucleosomes in ODC mice is unaffected, implying that access by histone modifying enzymes is not generally restricted. The abnormal chromatin environment fostered by elevated levels of polyamines may be a necessary prerequisite for epithelial tumor growth and maintenance.

Acetylation↗
PubMed1997

Decrease in myocardial polyamine concentration in rats with myocardial infarction.

Cardiac polyamines are thought to protect the myocardium against harmful stimuli and to be regulated by sympathetic nerve activation. In the present study, polyamines concentrations in non-infarcted myocardium were investigated. Myocardial polyamines contents decreased significantly in the non-infarcted regions by day 3 in rats with myocardial infarction compared with sham-operated rats and with the untreated control rats. The cardiac catecholamine concentration decreased by day 1 after myocardial infarction. Myocardial ornithine decarboxylase activity also decreased in the non-infarcted regions; suggesting that the decrease in cardiac polyamines contents relate to an insufficiency of the ornithine decarboxylase activity in rats with myocardial infarction. These results suggest that the decrease in polyamines concentrations after myocardial infarction is associated with functional sympathetic nerve denervation and that the vulnerability of the heart after myocardial infarction may be due to a decrease in polyamine concentrations in the non-infarcted region.

Animals↗
PubMed1995

Polyamine oxidase, properties and functions.

Polyamine oxidase (PAO) is a FAD-dependent enzyme with a molecular mass of about 62 kDa, present with high activity in most tissues of vertebrates. Structural requirements of a substrate for PAO are two positively charged amino groups, separated by a short carbon chain and an alkyl substituent on one or both nitrogen atoms. Spermine and the monoacetyl derivatives N1-acetylspermine and N1-acetylspermidine appear to be the natural substrates. Spermidine is only poorly oxidized by PAO. Using O2, the substrates are oxidatively cleaved by PAO to form equimolar amounts of an amine, an aldehyde and hydrogen peroxide. PAO is an integral part of the polyamine interconversion cycle, a major intracellular regulatory system, which contributes to the maintenance of polyamine homeostasis in non-proliferating cells, including brain cells. Selective inactivators were used as tools in the elucidation of the functions of PAO. Interestingly, even long-term inactivation of PAO did not provoke behavioral changes in experimental animals, despite considerable changes in polyamine metabolism. PAO inactivation, however, improves the growth-inhibitory effects of inhibitors of polyamine biosynthetic enzymes and the antitumoral effects of some structural analogs of the polyamines.

Age Factors↗
PubMed1998

Complex polyamine effects on [3H]MDL 105,519 binding to the NMDA receptor glycine site.

Several studies have suggested that polyamines modulate the interaction of glycine with the NMDA receptor. We have further investigated the effects of polyamines using the NMDA receptor glycine site antagonist [(E)-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1H-indole-2-carbox ylic acid] ([3H]MDL 105,519). [3H]MDL 105,519 binding assays were performed using well washed membranes prepared from frozen rat brains. The polyamines spermine and spermidine increased the fraction of non-specific binding (determined by the addition of 1 mM glycine) in the [3H]MDL 105,519 binding assay from 40-60% when spermine or spermidine concentration was increased from 1 to 100 microM. Polyamine agonists spermine, spermidine and 1,5-(diethylamino)piperidine (30 microM) did not have a significant effect on displacement of [3H]MDL 105,519 binding by glycine or glycine site antagonists. Similarly, the polyamine antagonist arcaine did not have a significant effect on displacement of [3H]MDL 105,519 binding by glycine or glycine site antagonists. However, spermidine significantly depressed the potency of MDL 105,519 in displacing [3H]dizocilpine binding. These data suggest that [3H]MDL 105,519 may preferentially bind to a polyamine insensitive form of the NMDA receptor.

Aminoquinolines↗
PubMed1999

Multidrug resistance modifies polyamines uptake in P388 murine lymphoma cells: experimental and modeling approach.

Polyamines (putrescine, spermidine and spermine) are ubiquitous compounds, essential for cell growth. This paper compares the polyamine transport between sensitive P388 murine lymphoma cells and two multidrug resistant P388 sublines with the assistance of an experimental model. This new model allows the characterisation of the whole polyamines uptake and efflux. Three parameters are identified by the model: two rate constants (K+ for the uptake and K- for the efflux) which are considered as physical constants specific to the transport of one polyamine in one cell type, and Ci(o) which represents the initial intracellular concentration. This model well describes our experimental results of polyamine transport across the P388 cell plasma membrane. Multidrug resistant P388 cells exhibit spermine uptake significantly higher than that of sensitive cells when on the opposite, putrescine enters more rapidly into the sensitive P388 cells. In conclusion, comparison of polyamine transport between sensitive and multidrug resistant P388 phenotypes shows large and significant differences.

Animals↗
PubMed1998

Simultaneous assay of ornithine decarboxylase and polyamines after central nervous system injury in gerbil and rat.

Ornithine decarboxylase (ODC) is considered the rate-limiting enzyme in polyamine biosynthesis. An increase in putrescine (a natural polyamine) synthesis after central nervous system (CNS) injury appears to be involved in blood-brain barrier dysfunction, development of vasogenic edema and neuronal death. An improved method is described to determine the ODC activity as well as polyamine levels from the same brain tissue. The polyamine results showed no significant differences from data obtained with the conventional assay. The advantages of this method are to: (1) minimize the number of animals needed for the study, and (2) eliminate any internal inconsistencies resulting from use of two independent groups of animals for ODC and polyamine measurements. Using this method, ODC activities and polyamine levels were measured in cortices and hippocampi from global transient ischemia of gerbils and traumatic brain injury (TBI) of rats.

Animals↗