S-adenosylmethionine Decarboxylase Activity Research Articles

The effect of the polyamine biosynthesis inhibitor DFMO on the ectomycorrhizal fungus Paxillus involutus

DFMO reduced mycelial growth of the ectomycorrhizal fungus Paxillus involutus. This was accompanied by reduced activities of ornithine decarboxylase, S-adenosylmethionine decarboxylase and diamine oxidase, and unchanged polyamine oxidase activity. Although DFMO treatment did not alter putrescine or spermidine concentrations significantly, spermine concentration was substantially reduced.

Role of ethylene on induction and expression of carrot somatic embryogenesis: relationship with polyamine metabolism

The effects of ethylene on somatic embryogenesis were investigated during the induction phase (with auxin) and expression phase (without auxin) in carrot ( Daucus carota L.) cell cultures. The addition of 2-chloroethylphosphonic acid (CEPA), an exogenous source of ethylene, during the induction phase or after day 7 of the expression phase did not affect the level of somatic embryogenesis. However, an increase of ethylene concentration at the begining of the expression phase inhibited embryo formation. During this same period, ethylene reduced the polyamine formation from [U- 14C]arginine by inhibiting the activities of arginine decarboxylase (ADC, EC 4.1.1.19) and S-adenosylmethionine decarboxylase (SAMDC, EC 4.1.1.50). Furthermore, the addition of exogenous spermidine to ethylene-treated cells can restore the embryogenic potential of carrot cells. The results demonstrate that there is a physiological relationship between ethylene, polyamine biosynthesis and somatic embryogenesis.

TGF-β1 inhibits polyamine biosynthesis in K 562 leukemic cells

The present study proved that TGF-beta 1 significantly inhibited the growth of K 562 cells. The drop in cell numbers after 24 h incubation with increasing concentrations of TGF-beta 1 (0.01, 0.1, 1.0, 10.0 ng/ml) was accompanied by significant suppression of the activity of two key enzymes of polyamine biosynthesis: ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). In contrast to ODC and SAMDC activity, TGF-beta 1 did not significantly affect the absolute concentration of spermidine and spermine in K 562 cells. We suppose that the lack of an evident drop in concentration of spermidine and spermine in spite of a significant decrease in ODC and SAMDC activity in K 562 cells exposed to TGF-beta 1 resulted from the uptake of polyamines from the extracellular space.

The Effect of Ornithine Decarboxylase Inhibition on Growth, Enzyme Activities, and Polyamine Concentrations in Crinipellis perniciosa

Growth, polyamine concentrations, and the activities of enzymes of polyamine biosynthesis and breakdown were examined in the agaric Crinipellis perniciosa (Stahel) Sing., the causal agent of witches′-broom disease of cocoa (Theobroma cacao L.), that had been grown in the presence of the following irreversible inhibitors of ornithine decarboxylase: difluoromethylornithine (DFMO), monofluoromethyl-dehydro-ornithine methyl ester (MFMOCH3), and 6-heptyne 2,5 diamine (RRMAP), and in the presence of difluoromethylarginine (DFMA), an irreversible inhibitor of arginine decarboxylase. All treatments reduced mycelial growth and depressed ornithine decarboxylase activity, but these events were not always directly linked to polyamine depletion. Putrescine concentration was markedly increased by DFMO but was not affected by DFMA and was decreased by both RRMAP and MFMOCH3. All treatments, apart from MFMOCH3, increased spermidine. No spermine was detectable in DFMO- and MFMOCH3-treated mycelia. All treatments, apart from DFMA, increased S-adenosylmethionine decarboxylase activity. The activities of di- and polyamine oxidase were increased by DFMO but not significantly affected by other treatments. It is suggested that the growth reduction induced by DFMO, DEMA, and RRMAP may be due, in part, to spermidine accumulation. In this scheme, the action of polyamine oxidase on spermidine would generate hydrogen peroxide and free radicals, both of which would induce membrane damage.

Effect of N-( n-butyl)-1,3-diaminopropane on polyamine metabolism, cell growth and sensitivity to chloroethylating agents

The effects of N-( n-butyl)-1,3-diaminopropane (BDAP) on cell growth and polyamine content were examined in L1210, SV-3T3 and HT-29 cells. In all cases, BDAP was a specific and highly effective inhibitor of spermine synthesis, and spermine levels were greatly suppressed in the presence of 50 μM BDAP. At the same time, there was a parallel increase in spermidine, which equalled or exceeded the fall in spermine so that total polyamine levels were not reduced. Cell growth was not affected in short-term experiments but culture of L1210 cells for 72–144 hr in the presence of BDAP did lead to an effect on growth that was reversed by the addition of spermine. These results suggest that, in the short term, a normal growth rate is maintained by spermidine but that a function or cellular component critically dependent on spermine becomes depleted at longer times. BDAP was a weak inducer of spermidine/spermine- N′-acethyltransferase and this enzyme may be responsible for exretion or degradation of the inhibitor. The reduction of spermine produced by BDAP led to a substantial increase in the activity of S-adenosylmethionine decarboxylase (AdoMetDC) showing that the repression of this enzyme by spermine is greater than the repression by spermidine. Although higher concentrations were required, BDAP was as effective an inhibitor of spermine synthesis as the mechanism-based inhibitor, S-adenosyl-1,12-diamino-3-thio-9-azadodecane (AdoDATAD), and produced similar decreases in spermine and increases in AdoMetDC. Prior treatment of HT-29 human colon carcinoma cells with BDAP increased the killing by chloroethylating agents but to a much smaller extent than the increase brought about by the DNA repair inhibitor, O 6-benzylguanine. The effect of BDAP is likely to be due to an increased interaction of chloroethylating drugs with nuclear DNA in the absebce of spermine since BDAP treatment sensitized cells even in the presence of O 6-benzylguanine, which prevents repair of these lesions.

4-Amidinoindan-1-one 2'-amidinohydrazone: a new potent and selective inhibitor of S-Adenosylmethionine decarboxylase.

Two isomeric amidino-2-acetylpyridine amidinohydrazones, 11 and 12, and 4-amidinoindanone amidinohydrazone, 17, have been synthesized and tested for inhibition of S-adenosylmethionine decarboxylase (SAMDC) and diamine oxidase and for antiproliferative activity against T24 human bladder carcinoma cells. Compound 11 inhibited SAMDC with an IC50 of 10 nM and was 140- and > 500-fold more potent than methylglyoxal bis(guanylhydrazone) (MGBG) and 12, respectively. The difference in potency between 11 and 12 was interpreted with the help of molecular modeling and appeared to be associated with two different low-energy conformations of the compounds. Compound 17 which represents a conformationally constrained analogue of 11, was superior to the latter and MGBG with respect to selective inhibition of SAMDC and antiproliferative activity, and is of interest as a potential anticancer agent and a drug for the treatment of protozoal and Pneumocystis carinii infections.

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 ( K m = 39 μM), 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.

Effects of inhibitors of spermidine synthase and spermine synthase on polyamine synthesis in rat tissues

Several inhibitors of aminopropyltransferases, developed recently in this laboratory, were tested for their specificity by measuring their effects on six enzyme activities related to polyamine biosynthesis and interconversion. Two of them, trans-4-methylcyclohexylamine (4MCHA) and N-(3-aminopropyl)cyclohexylamine (APCHA), selectively and potently inhibited the activities of spermidine synthase and spermine synthase, respectively. They were subjected to in vivo studies using rats. Oral administration of 4MCHA or APCHA dissolved in drinking water (0.02 and 0.1%) available ad lib. for a period of 10 days or 4 months caused a specific and marked decrease in spermidine or spermine in tissues (such as a 95% decrease) with a compensatory increase of spermine or spermidine, respectively, but without any observable change in the growth of the treated rats. Also, with extreme reduction of spermidine or spermine, when their sum was approximately constant, the activity of S-adenosylmethionine decarboxylase in these tissues was enhanced significantly with no change in the activity of ornithine decarboxylase. These results suggested a separate role for spermidine or spermine in the in vivo enhancement of S-adenosylmethionine decarboxylase activity.

Brain S-adenosylmethionine decarboxylase activity is increased in Alzheimer's disease

We measured the activity of S-adenosylmethionine decarboxylase (SAMDC), a key regulatory enzyme of polyamine biosynthesis, in autopsied brain from 13 patients with Alzheimer's Disease (AD). As compared with the controls, mean enzyme activity was increased by 37–96% in all seven examined brain regions with statistically significant increases in temporal cortex (+96%), frontal cortex (+69%) and hippocampus (+90%). The elevated SAMDC may have occurred as part of a generalized polyamine response to brain injury, which has been previously described in experimental animal conditions. Above-normal SAMDC activity implies increased levels/metabolism of spermidine and spermine, two polyamines which are involved in neuronal regeneration, growth factor production, and activation of excitatory N- methyl- d-aspartate preferring glutamate receptors. Our data suggest the involvement of the polyamine system in the brain reparative and/or pathogenetic mechanisms of AD.

Antileukemic effects of non-metabolizable derivatives of spermidine and spermine

To determine whether non-metabolizable derivatives of spermidine and spermine exert anticancer effects, L1210 leukemic mice were treated with 5,8-dimethylspermidine and 5,8-dimethylspermine. Both derivatives cured 5% of the leukemic mice. The increase in median survival time, however, was slight. In combination with α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, only 5,8-dimethylspermine had a favorable effect. Treatment with DFMO is known to increase the uptake of extracellular polyamines and presumably their derivatives, by depleting the intracellular putrescine and spermidine content. However, treatment of L1210 leukemia cells in vitro with SFMO did not affect the uptake of the methyl-substituted polyamines added to the growth medium. 5,8-Dimethylspermidine and 5,8-dimethylspermine repressed the ornithine decarboxylase activity when added to cultures of L1210 leukemia cells. S-Adenosylmethionine decarboxylase activity was only repressed by 5,8-dimethylspermine. This finding may explain the potentiation by this derivative and not by 5,8-dimethylspermidine, of the antileukemic effect of DFMO.

Effects of Polyamines on the Ice-nucleating Activity ofErwinia uredovoraKUIN-3

The effects of polyamines on the ice-nucleating activity of an ice-nucleating bacterium, Erwinia uredovora KUIN-3, were investigated. The activity in the outer membrane derived from this bacterium was increased by the addition of spermidine (10mM). Also, the activity was stabilized in alkaline pH buffer with the addition of polyamine. Further, the addition of methylglyoxal bis(guanylhydrazone) which inhibited the activity of S-adenosylmethionine decarboxylase, inhibited the ice-nucleating activity of the cells of this bacterium. The amount of polyamine in this bacterium was examined using HPLC. The components of the polyamines were three species, putrescine, cadaverine, and spermidine. The amounts of polyamines in the cells and outer membranes after MGBG treatment decreased. The results suggested that polyamine was the most important component of the ice-nucleating material in this bacterium.

Regulation of S-adenosylmethionine decarboxylase activity by alterations in the intracellular polyamine content.

The effects of addition of exogenous spermidine and spermine and of two inhibitors of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), which decreases spermidine concentrations, and n-butyl-1,3-diaminopropane, which depletes spermine, on the expression of S-adenosylmethionine decarboxylase (AdoMetDC) activity were studied in mammalian cell lines (HT29, CHO and COS-7). AdoMetDC levels were inversely related to the polyamine content, and spermine was the more potent repressor of AdoMetDC activity, but only spermidine affected the amount of AdoMetDC mRNA. Transfection of COS-7 cells or CHO cells with plasmid constructs containing a chloramphenicol acetyltransferase (CAT) reporter gene driven by portions of the AdoMetDC promoter region indicated that CAT expression was altered by spermidine, but not by spermine, suggesting that there is a spermidine-responsive element in this promoter. Transient transfection of COS-7 cells with pSAMh1, a plasmid containing the AdoMetDC cDNA in a vector with the SV40 promoter and origin of replication, led to a large increase in AdoMetDC expression. Although treatment of COS-7 cells with n-butyl-1,3-diaminopropane greatly increased endogenous AdoMetDC activity, the spermine depletion brought about by this inhibitor did not stimulate AdoMetDC expression from pSAMh1. The pSAMh1 cDNA is missing 72 nucleotides from the 5' end of the AdoMetDC mRNA, and it is possible that translational regulation by spermine involves this region. The expression of AdoMetDC from pSAMh1 in COS-7 cells was greatly inhibited by DFMO treatment, although endogenous AdoMetDC activity was increased. The expression of other plasmids containing the SV40 origin of replication was also inhibited by DFMO in COS-7 cells, but not in CHO cells. DFMO treatment did not interfere with the expression of plasmids driven by the RSV promoter. These results suggest that low spermidine levels interfere with the replication of plasmids containing the SV40 origin of replication.

Effect of putrescine on S-adenosylmethionine decarboxylase in a small intestinal crypt cell line.

Two key enzymes in polyamine biosynthesis are ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). SAMDC decarboxylates S-adenosylmethionine, which then donates aminopropyl groups for spermidine and spermine synthesis. The purpose of our study was to determine whether putrescine, taken up from medium or synthesized endogenously by ODC, alters SAMDC activity. Studies were conducted in the IEC-6 cell line derived from rat small intestinal crypt cells. Cells were grown in Dulbecco's minimal essential medium containing 5% dialyzed fetal bovine serum (dFBS). They were deprived of serum for 24 h before experiments. Basal SAMDC activity was increased significantly by > or = 10(-4) M of putrescine. Lower doses had no significant effect. The same doses of putrescine decreased ODC activity to near zero. Asparagine at 10 mM or 5% dFBS not only stimulated ODC activity and the intracellular putrescine levels but also increased significantly SAMDC activity as well. ODC activity peaked at 3 h, and the maximum level of SAMDC occurred 3-4 h after exposure to asparagine or serum. Treatment with DL-alpha-difluoromethylornithine (DFMO), a specific ODC inhibitor, prevented the increases in both cellular putrescine levels and SAMDC activity in asparagine- and serum-treated cells. In the presence of DFMO, exogenous putrescine returned SAMDC activity toward control levels but had no effect on ODC. A very slight increase of SAMDC half-life in IEC-6 cells grown in the presence of putrescine was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethylene-Induced Polyamine Accumulation in Rice (Oryza sativa L.) Coleoptiles

Effects of ethylene on free polyamine biosynthesis in rice (Oryza sativa L. cv Taichung Native 1) coleoptiles were investigated in sealed and aerobic conditions. In sealed conditions, putrescine increased significantly and coincided with ethylene accumulation. Application of ethylene in sealed containers promoted putrescine accumulation over that in sealed controls. This ethylene-enhanced putrescine accumulation was inhibited by the ethylene action inhibitor 2,5-norbornadiene at 4000 muL/L. In aerobic conditions, ethylene and 1-aminocyclopropane-1-carboxylic acid also induced putrescine accumulation. Activity of arginine decarboxylase (EC 4.1.1.19) and S-adenosylmethionine decarboxylase (EC 4.1.1.50) increased on exposure to ethylene in aerobic conditions. Ornithine decarboxylase (EC 4.1.1.17) activity, however, remained unchanged. The ethylene-induced putrescine accumulation was inhibited by 5 x 10(-4)m alpha-difluromethylarginine, but not by 5 x 10(-4)m alpha-difluromethylornithine. Apparently, arginine decarboxylase, not ornithine decarboxylase, mediates the ethylene-induced putrescine accumulation. The increased S-adenosylmethioinine decarboxylase activity, however, did not result in a significant spermidine/spermine accumulation. In ethylene-treated coleoptiles, the accumulation of putrescine paralleled the increase of coleoptile length in both sealed and aerobic conditions. alpha-difluromethylarginine inhibited ethylene induced putrescine accumulation and coleoptile elongation. It seems that putrescine biosynthesis might be involved in the ethylene-induced elongation of rice coleoptiles.

Activity of ornithine decarboxylase and S-adenosylmethionine decarboxylase in transient cerebral ischemia: Relationship to the duration of vascular occulusion

Mongolian gerbils were anesthetized with halothane and forebrain ischemia was induced by occluding both common carotid arteries. After 2, 4, 6, 8, or 10 min of vascular occlusion clips were removed and animals allowed to recover for 8 or 24 h. At the end of the experiments animals were reanesthetized and their brains frozen in situ. Tissue samples were taken from the cerebral cortex, striatum, hippocampus, and thalamus for determination of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activity by measurement of the release of 14CO 2 from [ 14C]ornithine and S-[ 14C]adenosylmethionine, respectively. A transient increase in ODC activity was found after 8 h of recirculation following cerebral ischemia in all brain structures studied. ODC activity was significantly increased after 8 h of recirculation in the hippocampus of animals subjected to 4 min of ischemia, in the cortex and striatum after 6 min of ischemia, and in the thalamus after 8 min of vascular occlusion. ODC activity had already reached a plateau in the hippocampus after 4 min of vascular occlusion and in the cortex, striatum, and thalamus after 8 min, since there is no further increase in activity even after 10 min of ischemia. After cerebral ischemia and 24 h of recirculation ODC activity returned to control levels throughout the forebrain regardless of the duration of ischemia. SAMDC activity was significantly reduced after 8 h of recirculation following 4 to 10 min of ischemia in the cortex and 8 min of ischemia in the striatum. After 24 h of recirculation a significant reduction of SAMDC activity was measured in the cortex of animals subjected to 8 or 10 min of ischemia, in the striatum following 6 or 10 min of ischemia, and after 10 min of ischemia in the hippocampus. In control animals the SAMDC/ODC activity ratio (as an index of the extent of the disturbance of polyamine synthesis) ranged between 54.3 ± 17.2 (thalamus) and 172.4 ± 54.7 (cortex). After only 4 min of ischemia and 8 h of recirculation this ratio declined to 2.8 ± 1.7 in the vulnerable hippocampus but was still between 26.2 ± 18.4 (cortex) and 39.9 ± 50.5 (striatum). It is suggested that studying ischemia-induced changes in ODC and SAMDC activity may provide new information about the molecular mechanisms underlying stress-induced changes in gene experession and protein synthesis.

Polyamine metabolism in different pathological states of the brain.

Biosynthesis of the polyamines spermidine and spermine and their precursor putrescine is controlled by the activity of the two key enzymes ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). In the adult brain, polyamine synthesis is activated by a variety of physiological and pathological stimuli, resulting most prominently in an increase in ODC activity and putrescine levels. The sharp rise in putrescine levels observed following severe cellular stress is most probably the result of an increase in ODC activity and decrease in SAMDC activity or an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Spermidine and spermine levels are usually less affected by stress and are reduced in severely injured areas. Changes of polyamine synthesis and metabolism are most pronounced in those pathological conditions that induce cell injury, such as severe metabolic stress, exposure to neurotoxins or seizure. Putrescine levels correlate closely with the density of cell necrosis. Because of the close relationship between the extent of post-stress changes in polyamine metabolism and density of cellular injury, it has been suggested that polyamines play a role in the manifestation of structural defects. Four different mechanisms of polyamine-dependent cell injury are plausible: (1) an overactivation of calcium fluxes and neurotransmitter release in areas with an overshoot in putrescine formation; (2) disturbances of the calcium homeostasis resulting from an impairment of the calcium buffering capacity of mitochondria in regions in which spermine levels are reduced; (3) an overactivation of the NMDA receptor complex caused by a release of polyamines into the extracellular space during ischemia or after ischemia and prolonged recirculation in the tissue surrounding severely damaged areas; (4) an overproduction of hydrogen peroxide resulting from an activation of the interconversion of spermidine into putrescine via the enzymes spermidine N-acetyltransferase and polyamine oxidase. Insofar as a sharp activation of polyamine synthesis is a common response to a variety of physiological and pathological stimuli, studying stress-induced changes in polyamine synthesis and metabolism may help to elucidate the molecular mechanisms involved in the development of cell injury induced by severe stress.

Methionine Intake in Rainbow Trout (Oncorhynchus mykiss), Relationship to Cataract Formation and the Metabolism of Methionine

Young rainbow trout were given diets containing graded levels of methionine for 16 wk. Analysis of the weight gain and food efficiency data showed the methionine requirement to be not more than 0.76% of the diet (1.9% of dietary protein). Activities of regulatory enzymes of the transulfuration pathway, methionine adenosyltransferase and cystathionine synthase in trout liver were not altered by changes in methionine intake. Concentrations of free serine in liver and plasma of the trout were high at low levels of methionine intake but fell as dietary methionine increased. This implied decreased flux through cystathionine synthase at low methionine intakes. Large increases in liver and plasma taurine occurred at high methionine intakes, implying enhanced transulfuration activity. Liver ornithine decarboxylase activity was reduced at the lowest level of dietary methionine used but the activity of S-adenosylmethionine decarboxylase was unchanged. Eye lenses of the trout given these diets were examined by a scanning lens monitor. Analysis of focal length variability with this equipment demonstrated that, if abnormality of the lens is to be avoided, a higher concentration of dietary methionine (0.96% or 0.6% methionine + 0.36% cystine) is needed than that required to maximize growth.

Senescence of Rice Leaves XXXII. Effects of Abscisic Acid and Benzyladenine on Polyamines and Ethylene Production during Senescence

Summary The effects of abscisic acid (ABA) and benzyladenine (BA) on polyamines and ethylene production during senescence of detached rice leaves under light were investigated. The senescence of rice leaves was followed by measuring the decrease of protein. BA (0.01 mM) significantly retarded and ABA (0.1 mM) markedly promoted senescence of detached rice leaves. Putrescine and spermine levels were increased (30 to 50 %) by ABA and decreased (30 to 50 %) by BA. However, spermidine level was found to be decreased (50 %) by ABA and increased (25 %) by BA. BA treatment had no effect on the activities of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC, but resulted in 20 to 50 % lower activity of arginine decarboxylase (ADC) when compared with the water controls. Both the activities of ODC and SAMDC were increased about 2–3 times by ABA during the 3rd and 4th day of incubation. ABA treatment resulted in a peak of ADC activity during the first 24 h of incubation. ABA inhibited but BA promoted ethylene production during senescence. It is concluded that (a) endogenous polyamine levels and polyamine biosynthetic enzyme activities are not correlated with rice leaf senescence, (b) the effect of ABA of BA on senescence are separated from that on polyamine levels or polyamine biosynthesis, and (c) polyamine and ethylene biosynthesis in rice leaves do not compete for the substrate, S-adenosylmethionine.

Comparison of androgen regulation of ornithine decarboxylase and S-adenosylmethionine decarboxylase gene expression in rodent kidney and accessory sex organs.

Androgen regulation of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) activities and accumulation of the mRNAs encoding these two enzymes in rodent kidney and accessory sex organs were studied. The ODC mRNA concentration and enzyme activity were increased by androgens in kidney, prostate, and seminal vesicle of 3-day castrated mice and rats, whereas AdoMetDC mRNA and protein levels were androgen inducible only in rodent accessory sex organs. ODC and AdoMetDC mRNAs were regulated in prostate and seminal vesicles in a coordinate fashion, with the maximal levels reached within 24-48 h of steroid exposure. The extent of induction was similar for the two gene products, and ODC and AdoMetDC mRNA accumulation occurred primarily in epithelial cells of accessory sex organs, as shown by in situ hybridization studies. The murine ODC promoter contains an androgen-responsive element (ARE)-like sequence at about -910 nucleotides from the cap site; this element binds to androgen receptor in vitro, albeit with much lower affinity than some other AREs. In transient expression studies with CV-1 cells, an ODC promoter construct (pODCCAT) conferred androgen responsiveness upon the reporter gene. ODC mRNA accumulation is androgen regulated in epithelial cells of proximal tubules in both murine and rat kidney; however, different subtypes of the proximal tubular cells respond in the two species, as revealed by in situ hybridization studies. Expression of the ODC gene was induced more markedly and for a longer duration in the murine than in the rat kidney, but the initial response occurred faster in the rat kidney. The relatively slow kinetics of ODC mRNA accumulation in mouse kidney were not due to recruitment of new cells to respond; rather, in situ hybridization studies indicated that there was progressive accumulation of the mRNA in the responding cells. Collectively, these data indicate that the genes for two key enzymes in polyamine biosynthesis are not regulated in an identical fashion in different androgen target tissues, such as rodent kidney and accessory sex organs.

Chronic lithium treatment prevents the dexamethasone-induced increase of brain polymine metabolizing enzymes

The paper describes the effects of various regimens of lithium chloride treatment on dexamethasone-induced increases in brain polyamine metabolizing enzymes. In contrast to peripheral tissues where acute lithium treatment suppresses the increase in ornithine decarboxylase activity, in the brain only chronic treatment was effective in preventing this increase and also the increases in the activities of S-adenosylmethionine decarboxylase and spermidine/spermine N 1-acetyltransferase. This findings indicate a novel brain target for lithium's action and in turn provide new avenues for exploring polyamine function in the brain.