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PubMed1992

High-performance liquid chromatographic determination of free polyamines in human seminal plasma.

Putrescine, spermidine and spermine were determined quantitatively in 192 ultrafiltered samples of human seminal plasma with a precision of +/- 1.9% by pre-column derivatization with benzoyl chloride and reversed-phase chromatography. The concentrations of free putrescine, spermidine and spermine ranged from 0 to 1.96 mmol/l (mean = 0.10), 0.017-0.96 mmol/l (mean = 0.16) and 0.13 to 20.80 mmol/l (mean = 2.43), respectively. A significant correlation between the amounts of spermidine and spermine was found (r2 = 0.806, P less than 0.0005). Otherwise, no significant correlations between free-polyamine levels and routine spermiogram parameters such as volume, sperm count, motility, vitality and morphology were obtained.

Adolescent↗
PubMed1993

In vivo effect of berenil on rat liver polyamine metabolism.

1. Berenil, administered to rats in vivo, promoted a decrease in liver SAMDC activity, but an increase in ODC and SAT activity. 2. Its effect on ODC was completely prevented by cycloheximide, that on SAT only partially. 3. Berenil had no effect on ODC activity in adrenalectomized rats. Adrenergic antagonists counteracted the effect of Berenil on ODC activity. 4. Polyamine content was increased. The maximum modification was observed for putrescine and N1-acetylspermidine.

Acetyltransferases↗
PubMedDate not supplied

Inhibition of ornithine decarboxylase activity decreases polyamines and suppresses DNA synthesis in human colonic lamina propria lymphocytes.

Ornithine decarboxylase (ODC) and the polyamines are essential for cell proliferation in a variety of cells including lymphocytes. In this study, we investigated the potential role of ODC and polyamines in human colonic lamina propria lymphocytes (LPL) compared to peripheral blood lymphocytes (PBL). Our results show that con A stimulation of LPL and PBL was associated with marked increases in ODC and polyamines. The specific inhibitor of ODC, alpha-difluoromethylornithine (DFMO), resulted in a complete inhibition of ODC activity and depletion of putrescine, spermidine and spermine levels. DFMO also suppressed DNA synthesis of LPL and PBL by up to 48% and 62% respectively. This antiproliferative effect was reversed by adding back the polyamines putrescine (1 mM), spermidine (10 microM) or spermine (10 microM) to the culture medium. We conclude that ODC and the polyamines are important for human LPL proliferation, and hence may play a role in human mucosal immune function.

Aged↗
PubMed1995

Brain polyamine levels are altered in Alzheimer's disease.

Despite considerable evidence implicating polyamines in CNS function, little is known about the status of the polyamine system in normal or abnormal human brain. We measured the levels of the polyamines spermidine, spermine and their precursor putrescine, in cortical and subcortical areas of 12 patients with Alzheimer's disease (AD). As compared with the controls, mean levels of spermidine were markedly and significantly increased (70%) whereas putrescine levels were decreased (28%) in temporal cortex of the AD patients. No other statistically significant changes were observed with the exception of a mean 35% reduction in spermine concentration in occipital cortex. In view of the modulatory effects of polyamines on calcium flux and glutamate receptor function, our data suggest that abnormal polyamine system activity may be involved in the neurodegenerative processes occurring in brain of patients with AD.

Aged↗
PubMed1990

Abnormal urinary excretion of polyamines in HHH syndrome (hyperornithinemia associated with hyperammonemia and homocitrullinuria).

The HHH syndrome (hyperornithinemia associated with hyperammonemia and homocitrullinuria) is characterized by a very rare genetic defect of ornithine transport in mitochondrial membrane. We first demonstrated that a patient with HHH syndrome excreted about 6 times higher amount of polyamines in urine than the control when supplemented with high protein diets and ornithine loading. Each urinary polyamine fraction measured by HPLC method in HHH syndrome appears to be increased, as compared with those of the control. These data suggest that increased urinary excretion of polyamines in this syndrome is closely related to overflowing of plasma polyamine due to an ornithine transport defect in the mitochondrial membrane.

Adolescent↗
PubMed2002

Polyamine uptake is necessary for a normal biochemical maturation of astrocytes in culture.

In this study we have explored the importance of polyamine uptake in the proliferation and biochemical maturation of cerebellar astroyctes in culture. The uptake of polyamines paralleled astrocyte proliferation measured as [3H]thymidine incorporation into the DNA. Inhibition of polyamine uptake did not alter the developmental profile of thymidine incorporation, perhaps due to a compensatory increase in ornithine decarboxylase activity but was able to reduce glutamine synthetase (GS) activity, an enzymatic marker for astrocyte biochemical maturation, from 9 days in vitro. The present results suggest that polyamine uptake plays an important role in the biochemical maturation of astrocytes in culture.

Animals↗
PubMed2007

Agmatine transport into spinal nerve terminals is modulated by polyamine analogs.

Agmatine (decarboxylated arginine) is an endogenous amine found in the CNS that antagonizes NMDA receptors and inhibits nitric oxide synthase. Intrathecally administered agmatine inhibits hyperalgesia evoked by inflammation, nerve injury and intrathecally administered NMDA. These actions suggest an antiglutamatergic neuromodulatory role for agmatine in the spinal cord. Such a function would require a mechanism of regulated clearance of agmatine such as neuronal or glial uptake. Consistent with this concept, radiolabeled agmatine has been shown to accumulate in synaptosomes, but the mechanism of this transport has not been fully characterized. The present study describes an agmatine uptake system in spinal synaptosomes that appears driven by a polyamine transporter. [(3)H]Agmatine uptake was Ca(2+), energy and temperature dependent. [(3)H]Agmatine transport was not moderated by L-arginine, L-glutamate, glycine, GABA, norepinephrine or serotonin. In contrast, [(3)H]agmatine uptake was concentration dependently inhibited by unlabeled putrescine and by unlabeled spermidine (at significantly higher concentrations). Similarly, [(3)H]putrescine uptake was inhibited in a concentration-dependent manner by unlabeled agmatine and spermidine. The polyamine analogs paraquat and methylglyoxal bis (guanylhydrazone) inhibited, whereas the polyamine transport enhancer difluoromethylornithine increased, [(3)H]agmatine transport. Taken together, these results suggest that agmatine transport into spinal synaptosomes may be governed by a polyamine transport mechanism.

Agmatine↗
PubMed1991

Adaptive response of ileal mucosa to malnutrition in the rat: role of polyamines.

Mucosal disaccharidases and ornithine decarboxylase activities were measured in malnourished, preweaning (19 days), post weaning (24 days) and young adult (37 days) rats. Malnutrition resulted in decreased body weight, intestinal weight, DNA and protein content. Mucosal Prot/DNA ratios were elevated in the ileal segments of the 24 and 37 day rats. Preweaned malnourished rats had significantly enhanced lactase specific activity in both jejunal and ileal segments. Adult malnourished rats showed enhanced jejunal lactase and sucrase activities which were not accompanied by elevated ornithine decarboxylase values. Mucosal sucrase and ornithine decarboxylase specific activities were significantly elevated in the ileal segment of the 24 and 37 day old malnourished rats. Studies of adult rats showed that these increased specific activities were located in the mature enterocytes at the villus tip, and persisted during a 24 h diurnal cycle. DFMO administration for 4 days completely inhibited mucosal ornithine decarboxylase and abolished the rise of ileal sucrase activity. We concluded that the intestinal response to reduced food intake is age related and differs in the jejunum and ileum: ornithine decarboxylase and polyamines are involved in ileal adaptation to malnutrition in postweaned and adult rats.

Adaptation, Physiological↗
PubMed1994

Effects of 2,5-dimethylpyrazine on plasma testosterone and polyamines- and acid phosphatase-levels in the rat prostate.

The effects of 2,5-dimethylpyrazine (DMP) on plasma testosterone and levels of polyamines and acid phosphatase in the prostate of rat were studied. A high dose of DMP administered once daily for two weeks to juvenile male rats significantly decreased plasma testosterone and levels of polyamines and acid phosphatase in the prostate. These effects were not obtained by administration to mature male rats, and the inhibition was thus recognized to occur during the growth period. These findings suggest that a high dose of DMP inhibits the biosynthesis of polyamines and acid phosphatase in the prostate by decreasing the circulating testosterone level.

Acid Phosphatase↗
PubMed1991

Polyamines: from molecular biology to clinical applications.

The polyamines putrescine, spermidine and spermine represent a group of naturally occurring compounds exerting a bewildering number of biological effects, yet despite several decades of intensive research work, their exact physiological function remains obscure. Chemically these compounds are organic aliphatic cations with two (putrescine), three (spermidine) or four (spermine) amino or amino groups that are fully protonated at physiological pH values. Early studies showed that the polyamines are closely connected to the proliferation of animal cells. Their biosynthesis is accomplished by a concerted action of four different enzymes: ornithine decarboxylase, adenosylmethionine decarboxylase, spermidine synthase and spermine synthase. Out of these four enzyme, the two decarboxylases represent unique mammalian enzymes with an extremely short half life and dramatic inducibility in response to growth promoting stimuli. The regulation of ornithine decarboxylase, and to some extent also that of adenosylmethionine decarboxylase, is complex, showing features that do not always fit into the generally accepted rules of molecular biology. The development and introduction of specific inhibitors to the biosynthetic enzymes of the polyamines have revealed that an undisturbed synthesis of the polyamines is a prerequisite for animal cell proliferation to occur. The biosynthesis of the polyamines thus offers a meaningful target for the treatment of certain hyperproliferative diseases, most notably cancer. Although most experimental cancer models responds strikingly to treatment with polyamine antimetabolites--namely, inhibitors of various polyamine synthesizing enzymes--a real breakthrough in the treatment of human cancer has not yet occurred. It is, however, highly likely that the concept is viable. An especially interesting approach is the chemoprevention of cancer with polyamine antimetabolites, a process that appears to work in many experimental animal models. Meanwhile, the inhibition of polyamine accumulation has shown great promise in the treatment of human parasitic diseases, such as African trypanosomiasis.

Adenosylmethionine Decarboxylase↗
PubMed1992

Polyamine metabolism in reversible cerebral ischemia.

Synthesis of the polyamines putrescine, spermidine, and spermine is controlled by the activity of the key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). Beside their function in cellular growth processes, polyamines and particularly putrescine play a role in calcium-related events at the cell membrane, coupling an extracellular stimulus to an intracellular response (second messenger-like reactions), modulate the calcium-buffering capacity of mitochondria (spermine), and, if present in the extracellular compartment, modulate the activity of the N-methyl-D-aspartate receptor (spermidine and spermine). Reversible cerebral ischemia triggers pathological disturbances in polyamine metabolism that are characterized by a sharp increase in ODC synthesis, even in the most vulnerable hippocampal CA1 subfield in which overall protein synthesis is severely depressed at the same time, and a marked suppression of SAMDC synthesis in parallel with the inhibition of overall protein synthesis. ODC immunohistochemistry has revealed that the observed changes are neuronal responses to reversible ischemia. These changes in enzyme activities result in an overshoot in the formation of putrescine, the product of ODC activity. Spermine levels are significantly reduced in vulnerable brain structures after prolonged recirculation. In addition, evidence is accumulating that polyamines may be released from the cell during ischemia and after prolonged recirculation at a time when cell necrosis is apparent. This review will summarize the major features of ischemia-induced disturbances in polyamine metabolism and the possible consequences for the cells involved, taking into account that the underlying changes may be indicative of either the activation of a recovery process of neurons from the metabolic stress produced by reversible ischemia or pathological disturbances resulting in the manifestation of neuronal necrosis. Elucidating the mechanisms responsible for the postischemic disturbances in polyamine metabolism may lead to a better understanding of the molecular mechanisms involved in the development of neuronal necrosis after different pathological stimuli.

Animals↗
PubMed1990

Effect of endogenous and exogenous polyamines on organic cation transport in rabbit renal plasma membrane vesicles.

The effect of several polyamines on the transport of organic cations [N1-[3H]methylnicotinamide (NMN), [3H]NMN and 3H-tetraethylammonium, ([3H]TEA)] in rabbit renal brush border (BBMV) and basolateral membrane vesicles (BLMV) was studied using a rapid filtration assay. Under pH-driven conditions in BBMV, [3H]NMN transport was cis inhibited approximately 30% by the naturally occurring polyamines (cadaverine, putrescine, spermine and spermidine) and nearly 90% by methylglyoxal bis(guanylhydrazone) (MGBG), a synthetic polyamine, mepiperphenidol and cimetidine, classical organic cation transport inhibitors. In the absence of a pH gradient, the capability of these agents to block [3H]NMN transport was diminished. The capability of these compounds to translocate the membrane was assessed by examining the phenomenon of counterflow. TEA, mepiperphenidol and MGBG produced trans stimulation of TEA uptake, whereas putrescine did not. Kinetic studies revealed that both putrescine and MGBG affected the Km value for TEA transport while having a minimal effect on the Vmax value. These results are most consistent with competitive inhibition. The specificity of polyamine inactivation of organic cation transport was assessed by examining what effect they had on the transport of another brush border transporter, D-glucose. These agents did not inhibit D-glucose transport. In addition, the effect of polyamines on the transport of organic cations in BLMV was studied. Only MGBG, cimetidine and mepiperphenidol inhibited organic cation transport. The results indicate that endogenous polyamines cis inhibited the organic cation transporter in BBMV competitively, whereas the exogenous polyamine MGBG cis inhibited competitively and produced trans stimulation. In contrast in BLMV, only MGBG was an effective inhibitor.

Animals↗
PubMedDate not supplied

Antitumor activity of a novel synthetic polyamine analogue, N,N'-bis-[3-(ethylamino)-propyl]-1-7-heptane diamine: potentiation by polyamine oxidase inhibitors.

The requirement of the natural polyamines, putrescine, spermidine and spermine, for cell growth suggests that appropriate structural analogues of these compounds could serve as potential antiproliferative agents acting via polyamine antagonism. In this investigation, the antiproliferative activity of N, N'-Bis[3-(ethylamino)-propyl]-1-7-heptane diamine (BEPH), a synthetic polyamine analogue, was investigated employing HeLa cells in culture and L1210 leukemia in mice. BEPH inhibited the growth of HeLa cells with an IC50 of 0.25 microM during a four day culture period. This concentration of the compound was cytotoxic to the cells as evidenced by an 80% reduction in cloning efficiency. Only marginal changes in intracellular polyamine concentrations were observed during incubation with 0.25 microM BEPH. In both HeLa cells and L1210 cells in culture, incorporation of radioactive precursors into DNA, RNA and protein were reduced by BEPH. Inhibition of protein synthesis was discernible prior to inhibition of RNA and DNA in these cells. In mice inoculated i.p. with 10(5) L1210 cells on day 0, i.p. administration of 10.0 mg/kg of BEPH qd(X5) beginning on day 1 prolonged the survival time by 84% compared to controls. The same dose of the compound, in combination with 10.0 mg/kg of N,N'-bis-2-3-butadienylputrescine, an inhibitor of the polyamine catabolizing enzyme polyamine oxidase (PAO), produced a 100% cure rate. Similar results were obtained when BEPH was combined with N-methyl-N'-2-3-butadienylputrescine, another PAO inhibitor. Furthermore, animals cured of the leukemia by the combination chemotherapy were resistant to a subsequent challenge with L1210 cells, indicating the development of tumor "immunity". The striking antitumor activity along with the development of tumor immunity indicate that synthetic polyamine analogues have potential for development as antineoplastic agents.

Animals↗
PubMed1989

Hyperthermia, polyamine depletion, and inhibition of X-ray-induced DNA strand break repair.

We have recently demonstrated that HeLa cells that had been depleted of polyamines by treatment with inhibitors of polyamine biosynthesis were deficient in their ability to repair X-ray-induced DNA strand breaks. Since it had previously been demonstrated that hyperthermic shock also inhibited strand break repair following X irradiation and that hyperthermia resulted in a leakage of polyamines from cells, it seemed of interest to examine whether the inhibition of repair by hyperthermia was related to this loss of cellular polyamines. In the present paper it is demonstrated that both polyamine depletion and hyperthermia inhibit strand closure, and that a combined treatment further reduces the rate of repair. In cells not depleted of polyamines, repair is restored to normal levels if hyperthermia treatment is followed by a 4-h incubation at 37 degrees C before X irradiation. In polyamine-depleted cells, this 37 degrees C incubation does not result in a return of repair ability. Polyamine supplementation was not effective in reversing hyperthermia-dependent repair inhibition, and, in fact, restoration of repair in control cells following hyperthermic shock corresponded to a time at which polyamines show a maximum decrease in those cells. These results suggest that the inhibition of repair and the increased radiosensitivity observed in hyperthermically treated cells is not related to polyamine depletion. However, data further suggest that polyamine-depleted cells may have other alterations, perhaps in chromatin, which render them more sensitive to thermal inhibition of repair.

Biogenic Polyamines↗
PubMed1988

[Ornithine decarboxylase activity and polyamine content in human adenocarcinomas of the stomach and large intestine].

Ornithine decarboxylase (ODC) activity and polyamine content were studied in the intact mucosa and tumours of human stomach and large intestine adenocarcinomas. ODC activity has been found to be much higher in the neoplastic tissue than in the corresponding intact mucosa. Concentrations of polyamines in neoplasms were also higher than in mucosa. Interrelation was found between ODC activity polyamine content and degree of differentiation of the tumour cells in rectal adenocarcinomas.

Adenocarcinoma↗
PubMed1993

S-adenosylmethionine decarboxylase in human brain. Regional distribution and influence of aging.

Recent experimental animal studies have implicated brain polyamines as having roles in both brain development and human brain neurodegenerative conditions. In order to provide baseline information, in normal human brain, on one of the key polyamine synthesising enzymes, S-adenosylmethionine decarboxylase (SAMDC), we examined the sensitivity of this enzyme to various cofactors/inhibitors, its regional distribution, and influence of aging in neurologically normal autopsied human brain. SAMDC in normal human brain is similar to that reported in other mammalian cells with regard to substrate affinity (Km = 39 microM), marked sensitivity to putrescine activation (+600%), inhibition (methylglyoxalbisguanidine and MDL 73811), and pH optimum (7.2). There was an uneven distribution of enzyme activity in human brain, and of the 12 brain regions examined, the highest activity was observed in occipital, parietal, frontal and temporal cortices (36-58 pmol/h/mg protein); intermediate activity in cerebellar and insular cortex, pulvinar thalamus, caudate and putamen (12-27 pmol/h/mg protein); and lowest activity in medial-dorsal thalamus, lateral globus pallidus and white matter (< 11 pmol/h/mg protein). The influence of aging (1 day to 103 years) on SAMDC activity in occipital cortex, the region showing the highest activity in human brain (n = 59) was also determined. Enzyme activity increased by approximately 600% from age 6 months to near maximal levels at age 10 years, then remained generally unchanged up to 103 years. Since SAMDC is a key regulatory enzyme in the synthesis of spermidine and spermine, the marked increase in SAMDC activity in the neonate and the sustained high enzyme levels throughout adulthood, imply a role for these polyamines in both development and mature brain function.

Adenosylmethionine Decarboxylase↗
PubMed1989

Acetylated polyamines in lungs from rats with monocrotaline-induced pneumotoxicity.

Multiple lines of evidence implicate the polyamines, putrescine, spermidine, and spermine in the lung injury and hypertensive pulmonary vascular disease produced in rats by the pyrrolizidine alkaloid monocrotaline. While increases in lung polyamine content evoked by monocrotaline can be attributed in part to induction of the two rate-limiting enzymes in de novo polyamine synthesis, ornithine decarboxylase and S-adenosylmethionine decarboxylase, little attention has been paid to the role that catabolic interconversion processes might play in lung polyamine accumulation. Accordingly, the present study evaluated dose (10-60 mg/kg)- and time (0-21 days)-dependent effects of monocrotaline on lung contents of acetylated polyamines and on the activity of spermidine/spermine acetyltransferase (SAT), the enzyme affecting spermidine acetylation. A single subcutaneous injection of monocrotaline produced dose- and time-dependent increases in the lung content of N1-acetylspermidine. Neither N1-acetylspermine nor N1-acetylputrescine could be detected in lungs from control rats or from rats treated with monocrotaline. SAT activity also was increased in monocrotaline-treated rat lungs in a dose- and time-dependent manner that was closely related to increases in the lung burden of N1-acetylspermidine. As expected, monocrotaline also caused dose- and time-dependent elevations in the lung contents of the primary polyamines, putrescine, spermidine, and spermine. Right ventricular hypertrophy, an index of sustained pulmonary hypertension, did not develop in animals treated with 10 or 20 mg/kg monocrotaline despite elevations in the lung contents of putrescine and N1-acetylspermidine and increases in the activity of SAT. In contrast, 30 and 60 mg/kg monocrotaline provoked right ventricular hypertrophy accompanied by elevations in the primary polyamines, N1-acetyl spermidine and SAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1994

Polyamine potentiation and inhibition of NMDA-mediated increases of intracellular free Ca2+ in cultured chick cortical neurons.

Polyamine potentiation and inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ changes was studied in cultured chick cortical neurons. Spermidine and spermine potentiated the effect of saturating concentrations of NMDA and glycine. No effect of spermidine or spermine was observed in the absence of NMDA or in the presence of either kainate or quisqualate. Similarly, antagonism of the NMDA receptor complex with dizocilpine (an open channel blocker), or with competitive antagonists to the NMDA or glycine binding sites greatly attenuated or completely abolished the combined effects of polyamines plus NMDA and glycine. N-Acetylspermine and N-acetylspermidine, in the presence or absence of NMDA and glycine, were without effect. These data strongly suggest that spermidine and spermine are potent and selective agonists at the polyamine binding site. Putrescine and diethylenetriamine were ineffective as antagonists of NMDA-mediated intracellular free Ca2+ increases in the presence or absence of added spermine or spermidine. Arcaine and 1,10-diaminodecane, however, antagonized NMDA-mediated intracellular free Ca2+ increases in the presence and absence of spermine and spermidine, and therefore appear to act either as inverse agonists at the polyamine binding site or as open channel blockers of the NMDA receptor.

Animals↗