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PubMed1998

A novel technique for visualizing the intracellular localization and distribution of transported polyamines in cultured pulmonary artery smooth muscle cells.

The use of a combination of monofluorescein adducts of spermidine (FL-SPD) and spermine (FL-SPM) with confocal laser scanning microscopy (CLSM) provides a useful means for monitoring the fate and time-dependent changes in the distribution of transported polyamines within living cells. Polyamine-fluorescein adducts were synthesized from fluorescein isothiocyanate and the appropriate polyamine. Monofluorescein polyamine adducts (ratio 1:1) were isolated using thin layer chromatography, and the structure and molecular weight of the monofluorescein polyamine adducts were confirmed using NMR and mass spectroscopy, respectively. The covalent linkage of the fluorescent adduct moiety to SPD and SPM did not influence their rate of uptake by bovine pulmonary artery smooth muscle cells (PASMC). Similar to 14C-SPD and 14C-SPM, the rate of uptake of 14C-FL-SPD and 14C-FL-SPM in PASMC was temperature-dependent. Treatment for 24 h with difluoromethylornithine (DFMO), a selective blocker of the enzyme ornithine decarboxylase and an inducer of the polyamine transport system, significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM compared to that of control cells. When compared to control cells, treatment of PASMC with the pyrrolizidine alkaloid monocrotaline for 24 h also significantly increased the cellular uptake of 14C-FL-SPD and 14C-FL-SPM. On the other hand, 24 h treatment of PASMC with a polymer of SPM, a selective blocker of the polyamine transport system, or with free spermine, markedly reduced the cellular accumulation of 14C-FL-SPD and 14C-FL-SPM. After a 20-min treatment of PASMC with FL-SPD or FL-SPM, CLSM revealed that adduct fluorescence was localized in the cytoplasm of living cells. Treatment with DFMO increased the cytoplasmic accumulation of both FL-SPD and FL-SPM. In addition, the fluorescence observed in the cytoplasm of chinese hamster ovary cells (CHO) was significantly higher than that detected in the cytoplasm of their polyamine transport deficient variants (CHOMGBG). The results of this study provide the first evidence of the utility of a novel method for visualizing the uptake, distribution, and cellular localization of transported polyamines in viable cultured mammalian cells.

Animals↗
PubMedDate not supplied

Developmental regulation of the brain polyamine-stress-response.

A transient increase in brain polyamine metabolism, termed the polyamine-stress-response is a common response to stressful stimuli. Previous studies have implicated an over-reactive polyamine response as a component of the maladaptive brain response to stressful events, and as a novel molecular mechanism involved in the pathophysiology of affective disorders. 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. Additionally, an important characteristic of affective disorders is their age dependency, a phenomenon that may be correlated with a maladaptive regulation of the hypothalamic-pituitary-adrenocortical (HPA) neuroendocrine system. In the present study we measured the activities of the enzymes ornithine decarboxylase and S-adenosylmethionine decarboxylase as markers of polyamine synthesis and found that unlike adults, immature rats do not show the characteristic brain polyamine-stress-response. Instead of the characteristic increase observed in adults, ornithine decarboxylase activity in immature animals was reduced or remained unchanged (for up to 16 days of age) after a dexamethasone injection or restraint stress application. The ontogenesis of this ornithine decarboxylase response was brain region-specific, indicating its dependence on the stage of neuronal maturation. Animals treated with dexamethasone at 7 days of age, showed increased behavioral reactivity in the open-field test as adults and an attenuated increase in ornithine decarboxylase activity after a re-challenge with dexamethasone at age 60 days. The results indicate that: (1) the brain polyamine-stress-response is developmentally regulated and its ontogenesis is brain region-specific, indicating dependence on the stage of neuronal maturation; (2) the switch to a mature polyamine-stress-response pattern coincides with the cessation of the stress hyporesponsive period in the HPA system: (3) activation of the polyamine-stress-response, as in the mature brain, appears to be a constructive reaction, while its down-regulation, as in the developing brain, may be implicated in neuronal cell death; (4) an attenuated dexamethasone-induced increase in ornithine decarboxylase activity implicates an altered polyamine-stress-response in the maladaptive response of the brain to stressful events.

Adenosylmethionine Decarboxylase↗
PubMed1993

Polyamines and prostatic carcinoma: clinical and therapeutic implications.

The erythrocyte polyamines, spermidine and spermine, are known proliferation markers. The authors present their experience with polyamines and prostatic carcinoma. 229 patients with prostatic carcinoma had polyamine erythrocyte determination at diagnosis. Previous results confirmed a tendency to spermidine increase with tumor stage and a significant increase in spermine in metastatic and hormonal escape patients. No correlation was found between polyamine erythrocyte levels and hemoglobin, prostate-specific antigen or tumor grade. 148 prostatic carcinoma patients were followed up. Their pretreatment erythrocyte polyamine levels were correlated to progression. Patients (whatever stage) with rapid progression present significantly enhanced pretreatment erythrocyte spermine levels compared to patients with a favorable outcome. Polyamines are not only proliferation markers but are also necessary for cell division. The authors present their results on polyamine deprivation, combining a polyamine-free diet, polyamine synthesis inhibitors and intestinal tract decontamination, on in vivo tumor growth inhibition of the murine prostatic carcinoma Dunning Mat LyLu tumor model.

Adult↗
PubMed1976

[Determination of blood polyamines in patients with brain tumor -with special reference to relationship between varieties of tumors and concentrations of blood spermidine and spermine (author's transl)].

Examination of blood polyamines in 38 patients with brain tumor and 17 normal volunteers was carried out by columnar chromatography--cellulose acetate membrane electrophoresis. The upper limits of the normal values; M.+2S.D. of the blood polyamine concentrations in 17 normal volunteers, were less than 2.1 mg/ml for spermidine, less than 1.6 mg/ml for spermine, and less than 2.2 mg/ml for spermidine plus spermine. The values of blood polyamines in 21 cases with glioma were significantly higher than those in normal subjects (p less than 0.01). And in 14 out of them, the concentrations of the blood polyamines were higher than the maximum normal value. In one case with reticulum cell sarcoma, the concentrations of the blood polyamines were remarkably increased. In 2 out of 4 cases with metastatic brain tumor the concentration of the blood polyamines were higher than the upper limit of normal amount, and values of the blood polyamines in 4 cases with metastatic brain tumor were significantly higher than those in normal volunteers (p less than 0.05). In none of 2 cases with pituitary adenoma, 3 cases with meningioma, 4 cases with neurinoma, one case with hemangioblastoma, and one case with pinealoma, the values of the blood polyamines were significantly higher than those in normal volunteers. The CSF samples obtained from 9 patients with brain tumor, consisted of 6 gliomas (glioblastoma multiforme 2, anaplastic glioma 4), 1 teratoblastoma, 1 von Recklinghausen's disease (neurinoma and meningioma), and 1 craniopharyngioma, were analyzed for detection of polyamines, but no detectable amount was present in those cases.

Adult↗
PubMed1987

Inhibition of translation of mRNAs for ornithine decarboxylase and S-adenosylmethionine decarboxylase by polyamines.

The effect of spermidine and spermine on the translation of the mRNAs for ornithine decarboxylase and S-adenosylmethionine decarboxylase was studied using a reticulocyte lysate system and specific antisera to precipitate these proteins. It was found that the synthesis of these key enzymes in the biosynthesis of polyamines was much more strongly inhibited by the addition of polyamines than was either total protein synthesis or the synthesis of albumin. Translation of the mRNA for S-adenosylmethionine decarboxylase was maximal in a lysate which had been substantially freed from polyamines by gel filtration. Addition of 80 microM spermine had no significant effect on total protein synthesis and stimulated albumin synthesis but reduced the production of S-adenosylmethionine decarboxylase by 76%. Similarly, addition of 0.8 mM spermidine reduced the synthesis of S-adenosylmethionine decarboxylase by 82% while albumin and total protein synthesis were similar to that found in the gel-filtered lysate. Translation of ornithine decarboxylase mRNA was greater in the gel-filtered lysate than in the control lysate but synthesis of ornithine decarboxylase was stimulated slightly by low concentrations of polyamines and was maximal at 0.2 mM spermidine or 20 microM spermine. Higher concentrations were strongly inhibitory with a 70% reduction occurring at 0.8 mM spermidine or 150 microM spermine. Further experiments in which both polyamines were added together confirmed that the synthesis of ornithine and S-adenosylmethionine decarboxylases were much more sensitive to inhibition by polyamines than protein synthesis as a whole. These results indicate that an important part of the regulation of polyamine biosynthesis by polyamines is due to a direct inhibitory effect of the polyamines on the translation of mRNA for these biosynthetic enzymes.

Adenosylmethionine Decarboxylase↗
PubMed2005

Polyamines promote root elongation and growth by increasing root cell division in regenerated Virginia pine (Pinus virginiana Mill.) plantlets.

Polyamines have been demonstrated to play an important role in adventitious root formation and development in plants. Here, we present a detailed analysis of influence of exogenously added polyamines on adventitious root development and its relationship to cold tolerance in Virginia pine (Pinus virginia Mill.). Our results demonstrated that polyamines putrescine (Put), spermidine (Spd), and spermine (Spm) at 0.001 mM improve rooting frequency and promote root elongation. Put, Spd, and Spm at 0.01-1 mM decrease rooting frequency and reduce root elongation root elongation. Measurements of diamine oxidase (DAO, EC 1.4.3.6) and polyamine oxidase (PAO, EC 1.4.3.4) activities showed that higher DAO and PAO enzyme activities were obtained when high concentrations of polyamines were applied and when plantlets were treated for 5-7 week at 4 degrees C and 16 degrees C. Survival rate of plantlets increased with the treatment of polyamines at low temperature. Polyamines increased mitotic index of cells in root tips of regenerated plantlet cultured on medium containing 0.001 microM Put, Spd, or Spm, but did not increase mitotic index in tissues of needle tips of the same plantlets. These results demonstrated that polyamines promote root elongation and growth by increasing root cell division in regenerated Virginia pine plantlets.

Amine Oxidase (Copper-Containing)↗
PubMed1987

Trypanosoma brucei: polyamine oxidase mediated trypanolytic activity in the serum of naturally resistant cattle.

Trypanosoma brucei brucei are lysed when incubated in vitro in a mixture of bovine serum and polyamine. Normal bovine serum alone or polyamine alone does not show any trypanocidal activity. The bovine serum in the mixture can be replaced by purified polyamine oxidase, and addition of polyamine oxidase inhibitors blocks trypanolysis. Using this in vitro lysis test, it is shown that West African cattle which are resistant naturally to trypanosomiasis have a higher trypanolytic activity in their serum than do trypanosensitive cattle (P less than 10(-5]. Seric trypanolytic activity of individual animals remains stable when tested over a period of 18 months; moreover, it is not modified by trypanosome infection. Higher levels of seric polyamine oxidase in resistant cattle were demonstrated also by enzymatic analysis. The factors responsible for trypanolysis have been analyzed. Oxidation of spermidine by polyamine oxidase leads to the production of unstable aldehydes, acrolein, ammonia, O2-, HO, and H2O2. Acrolein and H2O2 show strong trypanolytic activity while the other products do not appear to be toxic for trypanosomes. The physiological importance of polyamine oxidase mediated trypanolysis is unclear; even at peak parasitemia in cattle (10(7) organisms/ml) it can be calculated that trypanosomes would not release enough spermidine for the generation of sufficient quantities of toxic degradation products. Additional polyamines could be released in serum from tissues damaged as a result of the infection.

Acrolein↗
PubMed1989

Heat shock stimulates polyamine oxidation by two distinct mechanisms in mammalian cell cultures.

Heat shock stimulates both exogenous and endogenous polyamine oxidation in mammalian cells, but by distinct biochemical mechanisms. Exogenously added polyamines are oxidized in serum via the temperature-dependent activation of a single class of enzymes, the copper-dependent amine oxidases. Endogenous polyamines undergo a two-step reaction sequence involving acetylation by a heat-inducible acetyltransferase and subsequent oxidation by a constitutively expressed, flavin-dependent polyamine oxidase. In both instances, polyamine oxidation generates hydrogen peroxide and reactive aldehydes which influence cell viability as demonstrated by inhibitor studies. Aminoguanidine, an inhibitor of the copper-dependent amine oxidases, confers protection to cells during either a severe 43 degrees C heat shock or a relatively nontoxic heat stress followed by incubation at 37 degrees C, all in the presence of exogenous spermidine. Specific inhibition of the endogenous polyamine oxidase will also confer partial survival protection after heat shock, but only in cultures that have been previously depleted of cellular glutathione. These data confirm that hyperthermic stress can generate an oxidative stress in mammalian cells via induction of polyamine oxidation. Further, through distinct extracellular and intracellular mechanisms, these temperature-dependent polyamine oxidation reactions can modulate cell viability.

Acetyltransferases↗
PubMed2005

Effect of natural and synthetic polyamines on ethanol intake in UChB drinker rats.

Because of the important glutamatergic mediation of the behavioral effects of ethanol, glutamatergic agents have attracted attention for the treatment of ethanol abuse and dependence in preclinical and clinical studies. In the present study, we investigated the effect of pharmacological doses of the natural polyamines putrescine, spermine, and spermidine and the synthetic polyamine N,N'-bis-(3-aminopropyl)cyclohexane-1,4-diamine (DCD) on alcohol consumption in a free-choice paradigm carried out in genetically high-ethanol-consumer UChB rats. Short 3-day treatment with either polyamine, administered p.o., significantly reduced ethanol intake without modifying water and food intakes. Neither polyamine was able to increase markedly blood acetaldehyde in rats submitted to a standard challenge dose of ethanol, to rule out a disulfiram-like effect. Besides, blood ethanol disappearance after a test dose of ethanol was not affected by the synthetic polyamine DCD. Long-term treatment with DCD dose-dependently reduced ethanol intake in UChB rats without producing any observable effect on overt behavior, food consumption, and total fluid intake. The present results indicate that pharmacological doses of polyamines can reduce ethanol consumption in genetically drinking rats without producing significant side effects, suggesting that modulation of brain N-methyl-d-aspartate receptors by polyamines could represent a suitable strategy to reduce appetite for ethanol. However, caution must be exercised in interpreting the results because polyamines can also affect neuronal excitability by acting at other receptor targets, such as AMPA and kainate receptors, as well as at some voltage-dependent ion channels.

Acetaldehyde↗
PubMed2026

Polyamines buffer labile iron to suppress ferroptosis.

Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

Ferroptosis↗
PubMed1999

Polyamine oxidase activity in lymphoid tissues of glucocorticoid-treated rats.

Glucocorticoids are known to negatively affect lymphoid tissues, in which they cause programmed cell death. Polyamine depletion, which occurs in glucocorticoid-treated animals by inhibition of biosynthesis and induction of acetylation, may represent a signal to thymocytes for progression into the apoptotic program. Since catalysis of polyamines by the catabolic pathway produces hydrogen peroxide as a by-product, it has been suggested that the apoptotic process may be, in part, due to oxidative stress as a result of hydrogen peroxide production. In order to verify whether polyamine oxidase (EC 1.5.3.11) may play a role in the process, we examined the activity of the enzyme in the thymus and spleen of glucocorticoid-treated rats. We administered dexamethasone (4 mg/kg) or two different doses of corticosterone (4 mg/kg or 30 mg/kg) to rats, which were killed 8 or 24 hr after hormone injection. We found that corticosterone and dexamethasone affected polyamine oxidase activity in both tissues, with an opposite dose-dependent effect of the natural hormone in the thymus. The decrease and increase in polyamine oxidase after the two doses of corticosterone were correlated with the absence and the occurrence of DNA fragmentation, respectively. Moreover, corticosterone affected polyamine oxidase activity earlier (8 hr) than dexamethasone (24 hr), but the synthetic hormone was more efficient than the natural hormone in thymic polyamine depletion. The polyamine oxidase response may represent an important event in lymphoid tissues after glucocorticoid treatment, suggesting a role of the enzyme in the catabolic effects exerted by the two hormones.

Animals↗
PubMed2005

Spermine oxidase SMO(PAOh1), Not N1-acetylpolyamine oxidase PAO, is the primary source of cytotoxic H2O2 in polyamine analogue-treated human breast cancer cell lines.

The induction of polyamine catabolism and its production of H2O2 have been implicated in the response to specific antitumor polyamine analogues. The original hypothesis was that analogue induction of the rate-limiting spermidine/spermine N1-acetyltransferase (SSAT) provided substrate for the peroxisomal acetylpolyamine oxidase (PAO), resulting in a decrease in polyamine pools through catabolism, oxidation, and excretion of acetylated polyamines and the production of toxic aldehydes and H2O2. However, the recent discovery of the inducible spermine oxidase SMO(PAOh1) suggested the possibility that the original hypothesis may be incomplete. To examine the role of the catabolic enzymes in the response of breast cancer cells to the polyamine analogue N1,N1-bis(ethyl)norspermine (BENSpm), a stable knockdown small interfering RNA strategy was used. BENSpm differentially induced SSAT and SMO(PAOh1) mRNA and activity in several breast cancer cell lines, whereas no N1-acetylpolyamine oxidase PAO mRNA or activity was detected. BENSpm treatment inhibited cell growth, decreased intracellular polyamine levels, and decreased ornithine decarboxylase activity in all cell lines examined. The stable knockdown of either SSAT or SMO(PAOh1) reduced the sensitivity of MDA-MB-231 cells to BENSpm, whereas double knockdown MDA-MB-231 cells were almost entirely resistant to the growth inhibitory effects of the analogue. Furthermore, the H2O2 produced through BENSpm-induced polyamine catabolism was found to be derived exclusively from SMO(PAOh1) activity and not through PAO activity on acetylated polyamines. These data suggested that SSAT and SMO(PAOh1) activities are the major mediators of the cellular response of breast tumor cells to BENSpm and that PAO plays little or no role in this response.

Acetyltransferases↗
PubMed2003

Induction of hypersensitive cell death by hydrogen peroxide produced through polyamine degradation in tobacco plants.

Screening immediate-early responding genes during the hypersensitive response (HR) against tobacco mosaic virus infection in tobacco (Nicotiana tabacum) plants, we identified a gene encoding ornithine decarboxylase. Subsequent analyses showed that other genes involved in polyamine biosynthesis were also up-regulated, resulting in the accumulation of polyamines in apoplasts of tobacco mosaic virus-infected leaves. Inhibitors of polyamine biosynthesis, alpha-difluoromethyl-ornithine, however, suppressed accumulation of polyamines, and the rate of HR was reduced. In contrast, polyamine infiltration into a healthy leaf induced the generation of hydrogen peroxide and simultaneously caused HR-like cell death. Polyamine oxidase activity in the apoplast increased up to 3-fold that of the basal level during the HR, and its suppression with a specific inhibitor, guazatine, resulted in reduced HR. Because it is established that hydrogen peroxide is one of the degradation products of polyamines, these results indicate that one of the biochemical events in the HR is production of polyamines, whose degradation induces hydrogen peroxide, eventually resulting in hypersensitive cell death.

Cell Death↗
PubMedDate not supplied

Polyamine metabolism and cancer.

Polyamines are aliphatic cations present in all cells. In normal cells, polyamine levels are intricately controlled by biosynthetic and catabolic enzymes. The biosynthetic enzymes are ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, and spermine synthase. The catabolic enzymes include spermidine/spermine acetyltransferase, flavin containing polyamine oxidase, copper containing diamine oxidase, and possibly other amine oxidases. Multiple abnormalities in the control of polyamine metabolism and uptake might be responsible for increased levels of polyamines in cancer cells as compared to that of normal cells. This review is designed to look at the current research in polyamine biosynthesis, catabolism, and transport pathways, enumerate the functions of polyamines, and assess the potential for using polyamine metabolism or function as targets for cancer therapy.

Acetyltransferases↗
PubMed1998

Changes in hepatic polyamine catabolism in elderly rats.

AIMS/BACKGROUND: Given the important role of polyamines (putrescine, spermidine, spermine) in the modulation of macromolecular syntheses, gene expression and proteolysis, alterations in their metabolic pathways could be relevant during senescence. Since the few existing data address mainly polyamine biosynthesis, we studied the oxidative catabolism of polyamines in the liver of rats 3-36 months of age. METHODS: Polyamine oxidase activity was fluorimetrically measured using N1-acetylspermine as substrate. Spermidine/spermine N1-acetyltransferase and diamine oxidase were measured by radiochemical methods using labeled acetyl-coenzyme A and putrescine, respectively, as substrate. Polyamines were separated by HPLC and fluorimetrically quantified after post-column derivatization with o-phthaldialdehyde. RESULTS: Spermidine/spermine N1-acetyltransferase activity increased in 36-month-old rats and polyamine oxidase activity in 24- and 36-month-old rats. A decline in spermine and increases in spermidine and putrescine in elderly rats suggested an activation of the interconversion pathway of higher into lower polyamines. The activity of diamine oxidase, which degrades putrescine, was enhanced starting from 12 months of age. CONCLUSION: In the liver of aged rats, an increase in the catabolic enzymes leads to a reconversion of the higher polyamines to putrescine. This increased catabolism may represent an important age-related change and may contribute to impairment of the expression of growth-related genes in senescence.

Acetyltransferases↗
PubMed2006

Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells.

Apple procyanidins have chemopreventive properties in a model of colon cancer, they affect intracellular signalling pathways, and trigger apoptosis in a human adenocarcinoma-derived metastatic cell line (SW620). In the present study we investigated relationships between procyanidin-induced alterations in polyamine metabolism and apoptotic effects. Apple procyanidins diminish the activities of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, key enzymes of polyamine biosynthesis, and they induce spermidine/spermine N(1)-acetyltransferase, which initiates retroconversion of poly-amines. As a consequence of the enzymatic changes polyamine concentrations are diminished, and N(1)-acetyl-polyamines accumulate in SW620 cells. In contrast with expectations MDL 72527, an inactivator of polyamine oxidase (PAO), improved the anti-proliferative effect of procyanidins, and caused an increase of the proportion of apoptotic cells, although it prevented the formation of hydrogen peroxide and 3-acetamidopropanal, the cytotoxic products of PAO-catalysed degradation of N(1)-acetylspermidine and N1-acetylspermine. Addition of 500 microM N1-acetylspermidine to the culture medium in the presence of procyanidins mimicked the effect of MDL 72527. Therefore we presume that the enhanced procyanidin-triggered apoptosis by MDL 72527 is mediated by the accumulation of N(1)-acetyl-polyamines. The observation that apple procyanidins enhance polyamine catabolism and reduce polyamine biosynthesis activity similar to known inducers of SSAT, without sharing their toxicity, and the potentiation of these effects by low concentrations of MDL 72527 suggests apple procyanidins for chemopreventive and therapeutic interventions.

Antineoplastic Agents↗
PubMed1999

Thiols and polyamines in the cytoprotective effect of taurine on carbon tetrachloride-induced hepatotoxicity.

The mechanism by which taurine (2-aminoethanesulfonic acid) protects hepatocytes injury induced by carbon tetrachloride (CCl4) is not fully understood. In a previous study, we reported that cellular polyamines play an important role in this mechanism. The relationship between cellular glutathione (GSH), protein-SH levels, and lactate dehydrogenase (LDH), with respect to the effect of polyamine on the cytoprotective ability of taurine in CCl4-induced toxicity in isolated rat hepatocytes, was examined. CCl4 induced a LDH release and decreased cellular thiols and polyamine levels. Treating with taurine reversed these depletions. The effect of CCl4 was also reversed by the addition of exogenous polyamines. Pretreating with alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, which is a key enzyme in polyamine biosynthesis and therefore used to deplete cellular polyamine, prevented the protective effect of taurine. Adding diethyl maleate, a cellular glutathione-depleting agent, reduced the effect of exogenous polyamines. The role of polyamine in the cytoprotective effect of taurine in CCl4-induced toxicity may therefore be by preventing, among others, GSH and protein-SH depletions.

Animals↗
PubMed1989

Inhibition of bone resorption by alpha-difluoromethylornithine may not be mediated by polyamine depletion.

We have examined the effect of alpha-difluoromethylornithine (DFMO) on bone polyamine content and parathyroid hormone (PTH)- and calcitriol-stimulated bone resorption in cultures of neonatal mouse calvaria. Polyamine content in bone homogenates was determined by reverse-phase paired-ion HPLC. Treatment with 5 mM DFMO for 48 h reduced putrescine from 0.4 nmol/bone to nondetectable levels, slightly decreased spermidine, and did not affect spermine. Bone resorption elicited by 48 h of treatment with PTH or calcitriol was inhibited by concentrations of DFMO greater than or equal to 5 mM added 48 h prior to hormone. This observation supported the concept that polyamines may play a role in bone resorption. However, other observations cast uncertainty on this conclusion. Measurement of calvarial polyamine content at 2 h intervals revealed no increase in endogenous polyamines for up to 10.5 h after calcitriol addition. Although addition of putrescine restored bone polyamine content, exogenous polyamines failed to reverse the inhibitory effects of DFMO on calcitriol-stimulated resorption. These results suggest that a mechanism other than depletion of polyamines could be contributing to the inhibitory effect of DFMO on resorption.

Animals↗