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At least 19 recordsLinked to original sources
PubMed1994

Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid.

Picolinic acid, a catabolite of L-tryptophan, is a potent co-stimulatory agent for the induction of tumoricidal activity and the production of L-arginine-dependent reactive nitrogen intermediates (RNI) in murine macrophages. We studied whether picolinic acid could affect nitric-oxide synthase (NOS) expression at the gene level in the macrophage cell line ANA-1. NOS mRNA was neither constitutively expressed nor induced by treatment with picolinic acid alone. However, low levels of NOS mRNA were induced by interferon (IFN)-gamma alone. In contrast, a major increase of NOS mRNA expression was observed after treatment with IFN-gamma plus picolinic acid. The synergism was already detectable after 5-6 h and increased up to 20 h of treatment. The ability of picolinic acid to augment IFN-gamma-dependent NOS mRNA expression was associated with a parallel increase in transcription, as demonstrated by nuclear run-on experiments. Protein synthesis was required for the induction of NOS mRNA because addition of cycloheximide dramatically reduced IFN-gamma plus picolonic acid-induced NOS mRNA expression. Finally, interleukin-4 significantly decreased IFN-gamma plus picolinic acid-induced NOS mRNA expression and NOS transcription. These data provide evidence of a molecular event connecting arginine and tryptophan metabolic pathways in the generation of RNI, and they indicate that picolinic acid can induce transcriptional activation of gene expression.

Amino Acid Oxidoreductases↗
PubMed1981

Inhibition of RNA synthesis in Neurospora crassa hyphae treated with picolinic acid.

Picolinic acid, a metal-chelating agent, blocks the nuclei of germinating conidia of Neurospora crassa in the G1 phase. The addition of picolinic acid to exponentially growing cultures of N. crassa in glucose medium causes an immediate inhibition of growth. Concentrations higher than 50 mM completely inhibit growth of mycelia, whereas lower concentrations (20-30 mM) give only a partial inhibition. Picolinic acid, added at the concentration of 20 mM, immediately blocks the accumulation of stable RNA, while protein accumulation continues at an unchanged rate for at least 30 min and only thereafter is slightly inhibited. DNA accumulation rapidly slows down after the addition of the drug. The level of polyadenylated RNA decreases quickly after the addition of picolinic acid, and the rate of its synthesis also appears to be inhibited. Picolinic acid greatly affects the metabolism of stable RNA in N. crassa: both processing and transcription of rRNA are sequentially inhibited with a moderate accumulation of precursor rRNA. It is concluded that the effects of picolinic acid on the nuclear division cycle in Neurospora may be related to the requirement of specific gene products to enter the S phase, whose synthesis is inhibited following the reduction of polyadenylated RNA synthesis.

Centrifugation, Density Gradient↗
PubMed1995

Histological and ultrastructural changes in the rat brain following systemic administration of picolinic acid.

Picolinic acid was administered intraperitoneally in a dose of 30, 60, or 100 mmol, once every 24 h for 8 days. Histologically, under normal conditions as well as when picolinic acid was administered in a dose of 30 mmol the brain formations exhibited characteristic features. When picolinic acid was administered in a dose of 60 mmol or 100 mmol, the alterations were profound and developed selectively in hippocampus, being much less intense in the substantia nigra and striatum. In such cases, injuries of neuronal cell bodies were accompanied by symptoms of spongiosis. Within the hippocampus, the neuronal cell body injury was selectively restricted to the hilar and CA3 regions of stratum pyramidale. Tissue spongiosis was more intense at the granular layer, particularly within the hilus and in the mossy fiber area at CA3. Histochemically, a variable intensity of the reaction of succinic and alpha-glycerophosphate dehydrogenases was demonstrated. A decrease in their activities was observed in areas where the neuronal cell body injuries and spongiosis took place. No changes in the Ca-ATP-ase activity in brain formation after picolinic acid treatment were observed. Ultrastructurally, the changes within substantia nigra were manifested by neuronal cell bodies of the dark type and dendritic degenerations. Also less damaged neuronal cell bodies were seen. They were swollen, depleted of polyribosomes with dilated elements of RER and altered mitochondria. Some of the dendritic profiles were swollen with lucent cytoplasm. Most of the boutons in synaptic contact zones were unchanged. Most presynaptic terminals which were in junction with dark dendrites were swollen with or without crystal-like aggregates of synaptic vesicles.

Animals↗
PubMed1984

Changes in streptonigrin lethality during adaptation of Escherichia coli to picolinic acid. Correlation with intracellular picolinate and iron uptake.

Uptake studies with [14C]picolinate and 55Fe3+ have provided an explanation for the change in streptonigrin killing on adaptation of Escherichia coli to picolinate, in terms of the available iron within the cell. When picolinic acid is added to a growing culture of E. coli an interval of bacteriostasis ensues; this adaptation period is followed by resumption of exponential growth. Addition of picolinate (4 mM) to a log phase culture of strain W3110 gave protection from the lethal action of streptonigrin (30 microM) when the two agents were added simultaneously. In contrast streptonigrin killed cells that had adapted to picolinate; however, a preincubation of adapted W3110 with phenethyl alcohol protected the cells from streptonigrin lethality. [14C]Picolinate uptake studies showed that initially picolinate entered the cells, but that it was excluded from adapted cells; addition of phenethyl alcohol permitted the entry of picolinate into adapted W3110. The changes in streptonigrin killing parallel the changes in concentration of intracellular picolinate, which can chelate the iron required by streptonigrin for its bactericidal action. 55Fe3+ uptake studies showed that initially picolinate prevented iron accumulation by strain W3110, whereas adapted cells did take up iron in the presence of picolinate. Addition of phenethyl alcohol prevented any observed uptake of iron by adapted W3110. This modulation of iron transport by picolinate also affects streptonigrin lethality. Experiments with iron transport mutants showed that picolinate acted on both the enterochelin and citrate routes of uptake. Therefore picolinate affects the concentration of available iron within the cell both by (a) its intracellular presence resulting in chelation of iron and (b) its action on iron uptake; these effects explain the change in streptonigrin killing on adaptation of E. coli to picolinate.

Escherichia coli↗
PubMed1992

Action of picolinic acid and structurally related pyridine carboxylic acids on quinolinic acid-induced cortical cholinergic damage.

Picolinic acid, a pyridine monocarboxylic acid derived from tryptophan metabolism by the kynurenine pathway, was shown to block cortical cholinergic neurotoxicity induced by quinolinic acid (QUIN), a pyridine dicarboxylic acid yielded by the same pathway. This study examined the specificity of the anti-toxic effect of picolinic acid by comparing its effect with several structurally related mono- and dicarboxylic acids, and by evaluating its potential to influence cholinergic neurotoxicity produced by kainic, ibotenic and quisqualic acid. Picolinic acid or related agents were injected alone or in combination with a fixed dose of QUIN into the right nucleus basalis magnocellularis (nbM) of rats anesthetized with halothane. Cholinergic neurotoxicity was assessed 7 days post injection by measuring choline acetyltransferase (ChAT) activity in the frontoparietal cortex on the injected and uninjected side. In picolinate experiments, the staining of nbM neurons by acetylcholinesterase (AChE) histochemistry was also examined. Focal injections of QUIN depleted cortical ChAT activity and staining of AChE in the nbM. Co-injection of picolinic acid with QUIN attenuated the decline in these two cholinergic neuron markers. Isonicotinate (4-pyridine monocarboxylate), but not nicotinate (3-pyridine monocarboxylate), significantly attenuated QUIN's effect on cortical ChAT activity. Among several dicarboxylic acids examined, only dipicolinate (2,6-pyridine dicarboxylate) showed activity. It produced a modest QUIN-like effect, but in co-injection experiments it attenuated the QUIN-induced decrease in cortical ChAT. When co-injected into the nbM with a neurotoxic dose of kainic, ibotenic or quisqualic acid which produced a neurotoxic response comparable to that of QUIN, picolinic acid attenuated kainic acid-induced neurotoxicity, but not ibotenate or quisqualate neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Picolinic acid as a matrix for laser mass spectrometry of nucleic acids and proteins.

We found that picolinic acid is a very good matrix for matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry of oligonucleotides, proteins and tRNA. Among the oligonucleotides, picolinic acid was shown to be effective for homo-oligonucleotides, d(G)40 and d(C)60, and for mixed-base oligonucleotides up to 190 bases. In the case of the single-stranded oligonucleotides, and of double-stranded ones as well, only parent ions corresponding to single-stranded DNA were observed. The efficiency for MALDI of oligonucleotides using the picolinic acid matrix was superior to that using 3-hydroxypicolinic acid. MALDI of transfer RNA phenylalanine-specific (tRNA(Phe)), a 76-base ribonucleic acid, was detected with a signal-to-noise ratio of > 10. By comparison with 3-hydroxypicolinic acid the results with picolinic acid are notably superior for all oligonucleotides.

Base Sequence↗
PubMed1981

Zinc absorption in cattle with a dietary picolinic acid supplement.

The effect of picolinic acid and hydroxyquinolines in intestinal zinc absorption of cattle was studied. In contrast to reports of the absorption in rat and in man, picolinic acid did not enhance zinc absorption in cattle. In two calves suffering from Adema disease, the bovine parallel to Acrodermatitis enteropathica, hydroxyquinoline supplementation resulted in an increase in intestinal 65Zn absorption, while picolinic acid had no such effect. The results may indicate a difference in the zinc absorption mechanism between cattle and other species.

Acrodermatitis↗
PubMed1977

Control of growth by picolinic acid: differential response of normal and transformed cells.

Picolinic acid reversibly inhibits the growth of cultured cells. Fourteen other pyridine derivatives were ineffective or toxic. Untransformed normal rat kidney (NRK) cells are reversibly arrested in the G(1) stage of the growth cycle as shown by cell counts, mitotic index, [(3)H]thymidine incorporation, and flow microfluorometry. Flow microfluorometry was used to monitor the effects of picolinic acid on numerous other cell lines. Normal cells are blocked in G(1), whereas transformed cells show responses that are dependent upon the transforming virus and independent of species or origin of the cell line. Kirsten sarcoma virus-transformed cells are blocked in G(1). Simian virus 40-transformed cells progress to a G(2) block. Cells transformed by polyoma or Harvey sarcoma virus with Moloney virus coat have flow microfluorometry profiles that indicate blocks in both G(1) and G(2). Cells transformed with Moloney sarcoma virus are not blocked in a specific phase of the cell cycle. Picolinic acid does not change the levels of NAD(+) plus NADH; however, the growth inhibition by picolinic acid is partially overcome by nicotinamide. These results suggest that picolinic acid interacts with a specific growth control mechanism that may involve NAD(+) and that this control mechanism is altered by different transforming viruses in different manners.

Cell Division↗
PubMed1993

Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitro.

Since picolinic acid, a tryptophan metabolite yielded by the kynurenine pathway, selectively attenuates quinolinic and kainic acid excitotoxicity that is dependent on the presence of a glutamatergic afferent input, it was hypothesized that this agent may inhibit the presynaptic release of glutamate. Using superfused rat striatal slices, this study examined the potential of picolinic acid, and related pyridine monocarboxylic acids, to modify kainic acid-induced glutamate release. Kainic acid (0.25, 0.5 and 1.0 mM) stimulated the release of glutamate, an effect which was calcium dependent and was attenuated in the presence of the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxalene-2,3-dione (500 microM). Picolinic acid significantly decreased glutamic acid release evoked by exposure of striatal slices to 1 mM kainate in the presence of calcium. The inhibitory action of picolinic acid on kainate-induced release was also shared by nicotinic and isonicotinic acid. In the absence of external calcium, kainic acid-induced glutamate release was significantly reduced by approximately 65%. Under this condition, picolinic acid (100 microM) failed to influence kainic acid-induced release. Picolinic acid (100 microM) itself increased glutamate release by 35% over basal release. While the ability of picolinic acid to inhibit excitotoxin-induced release supports the notion that it may act presynaptically to modify excitotoxicity, lack of structural specificity in its action tends to cast doubt on this mechanism of action.

Animals↗
PubMed1989

An in vitro study of the effect of picolinic acid on metal translocation across lipid bilayers.

The effect of picolinic acid (pyridine-2-carboxylic acid) on the efflux of divalent metal ions from multilamellar liposomes was examined to determine the possible specificity and mechanism for its reported beneficial effects on the intestinal absorption and systemic metabolism of zinc. Extraliposomal picolinic acid increased the efflux of Zn, Cu, Co, Mn, Ni, Cd, Pb, Fe(II) and Ca from the vesicles. However, when picolinic acid was trapped with Co, Cu and Zn within the liposomes, the loss of metals was reduced. In a partition study, picolinic acid increased the aqueous solubility of Zn, Cu, Co and Cd at alkaline pH, but did not transfer the metal to an organic bulk phase of chloroform. It is proposed that picolinic acid does not act as an ionophore and that any effect it may have on zinc metabolism is dependent upon its unselective chelating properties, which may also lead to altered dietary and systemic compartmentation of other divalent cations.

Animals↗
PubMed1994

Picolinic acid blocks the neurotoxic but not the neuroexcitant properties of quinolinic acid in the rat brain: evidence from turning behaviour and tyrosine hydroxylase immunohistochemistry.

Previous results suggest that the tryptophan metabolite, picolinic acid may have the unusual properties of antagonizing the neurotoxic but not the neuroexcitant effects of another tryptophan metabolite, quinolinic acid in the central nervous system. The present experiments tested this possibility utilizing behavioural and tyrosine hydroxylase immunohistochemical techniques. In the first series of experiments, rats received injections of relatively high concentrations of 6-hydroxydopamine (12 micrograms in 1 or 2 microliters), quinolinic acid (120 nmol in 0.5 microliters), picolinic acid (480 nmol in 0.5 microliters) or co-treatments (0.5 microliters) with quinolinic (120 nmol) plus picolinic acid (480 nmol) into the region of the substantia nigra. Results revealed that 6-hydroxydopamine and quinolinic acid alone produced a large loss of tyrosine hydroxylase-positive cells in the pars compacta of the substantia nigra. Behavioural results for all 6-hydroxydopamine (n = 10) and for some quinolinate-treated rats (n = 5) revealed ipsi- and contraversive circling following amphetamine (1 mg/kg, i.p.) and apomorphine (0.5 mg/kg, s.c.), respectively, consistent with unilateral loss of dopamine cells in the substantia nigra. The remaining quinolinate-treated rats (n = 9) circled ipsiversively following either stimulant suggesting damage to the pars reticulata. Groups treated with picolinic acid alone (n = 6) or co-injected (n = 6) showed no loss of tyrosine hydroxylase-positive cells in the substantia nigra and no circling response to the stimulants. In the second series of experiments, low concentrations of quinolinic acid (2.5, 5.0, 7.5 nmol), picolinic acid (10, 20, 30 nmol), or the two together (7.5 plus 30 nmol, respectively) were microinjected (0.5 microliter) into the dorsal striatum and circling behaviour evaluated. These results revealed dose-dependent contralateral circling with either quinolinate or picolinate; co-injection of the two tryptophan metabolites also produced contralateral circling. It was concluded that picolinic acid blocks the neurotoxic but not the neuroexcitant effects of quinolinic acid.

Animals↗
PubMed1985

The iron-chelating agent picolinic acid enhances transferrin receptors expression in human erythroleukaemic cell lines.

Picolinic acid, a metal chelating molecule, was administered to human erythroleukaemic cell lines (K 562 and HEL) that were grown in serum-containing media. Picolinic acid inhibited both iron uptake and cell growth. Furthermore, picolinic acid was shown to markedly decrease the level of ferritin in the cells. In spite of the inhibition of cell growth, picolinic acid induced a marked increase in the transferrin-binding capacity of the cells. This phenomenon was due to a two-five-fold enhancement of the rate of transferrin receptor biosynthesis. Other iron-chelating compounds, capable of reducing the level of intracellular iron, also elicited a marked enhancement of the transferrin-binding capacity of the cells. However, the addition of iron, as ferric ammonium citrate, in the culture medium elicited a marked increase in the level of ferritin and a strong decrease in the transferrin-binding capacity of the cells. On the basis of these data we propose that a feed-back mechanism is involved in the regulation of transferrin receptors: when the cells accumulate iron they decrease the number of transferrin receptors in order to prevent further accumulation of iron; when no or low iron is available to the cells, the number of transferrin receptors markedly increases as a compensatory mechanism.

Cell Line↗
PubMed1975

Inhibition of dopamine beta-hydroxylase in blood vessels by picolinic acid derivatives in vivo and their anthypertensive effects.

The effect of picolinic acid derivatives, 5-butylpicolinic (fusaric) acid (FA), 5-(3',4'-DIBROMOBUTYL)PICOLINIC ACID(BPR2FA)and 50(N'N-dimethyldithiocarbamoilmethyl)picolinic acid (YP-279) on dopamine beta-hydroxylase in blood vessels in vivo was studied. Maximum inhibition of the conversion of 14C-dopamine (14C-DA) to 14C-norepinephrine (14C-ne) in rat aorta, mesenteric artery and renal artery was detected 30 min after FA and Br2FA (75 mg/kg) and 60 min after YP-279 (75 MG/KG). NE synthesis from 14C-DA returned to near control values by 6 hr in the blood vessels. NE levels of the aorta and mesenteric artery were sigkificantly reduced by 30 to 50% at 4 hr after Br2FA or FA (75 mg/kg). Dopamine beta-hydroxylase (DBH) activity, using tyramine as substrate, in heart, aorta, mesenteric artery and renal artery was markedly reduced. The concentrations of FA, Br2FA and YP-279 in rat blood following a single i.p, injection of each drug increase rapidly, reaching highest values in 0 to 30 min and decreasing slowly to 0 after 6 hr. These compounds did not affect the uptake of 3H-NE into the rat heart. These three compounds were found to lower blood pressure effectively in normal Wistar rats (above 25 mg/kg).

Animals↗
PubMed1990

Picolinic acid, a catabolite of tryptophan, as the second signal in the activation of IFN-gamma-primed macrophages.

We have studied the effects of picolinic acid, a product of tryptophan degradation, on the activation of mouse peritoneal macrophages (M phi). Picolinic acid acts synergistically with IFN-gamma in activating M phi from C57BL/6 mice. Moreover, M phi from C3H/HeJ mice and C3H/HeN that do not become cytotoxic in response to IFN-gamma alone could be fully activated by exposure to picolinate plus IFN-gamma. These results indicate that picolinic acid is a potent costimulator of M phi activation that functions as a second signal. Inasmuch as we have previously demonstrated that the activation of cytotoxic M phi correlates with specific changes in ribosomal RNA (rRNA), we investigated whether picolinic acid could modify M phi RNA metabolism. Picolinic acid inhibited the synthesis of total M phi RNA, the accumulation of newly synthesized 28S rRNA, and augmented the steady state levels of rRNA precursors (pre-rRNA). These changes in RNA metabolism were similar to those previously described in murine M phi activated in vitro or in vivo to express tumoricidal activity. These results demonstrate that picolinic acid is a potent, biologic M phi second signal, suggest that the changes in rRNA are causally connected with the expression of tumoricidal activity, and suggest the existance of an autocrine effect mediated by picolinic acid.

Animals↗
PubMed1993

Picolinic acid, a catabolite of L-tryptophan, is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophages.

In this study we investigated the effects of picolinic acid, a catabolite of L-tryptophan, on the production of L-arginine-derived reactive nitrogen intermediates in the murine macrophage cell line ANA-1. ANA-1 macrophages did not produce nitrite (NO2-) constitutively, but accumulated detectable levels of NO2- on exposure to IFN-gamma. Picolinic acid, although ineffective by itself, augmented IFN-gamma-induced NO2- production. The activity of picolinic acid was evident at 1 mM and reached its maximum at 4 mM. Picolinic acid also augmented the IFN-gamma-dependent expression of TNF-alpha mRNA, but did not appreciably affect the secretion of the TNF-alpha protein. Neutralizing concentrations of anti-TNF mAb completely abrogated IFN-gamma- and IFN-gamma plus rTNF-alpha-induced NO2- production in ANA-1 macrophages, but only decreased by approximately 50% the synergistic interaction between IFN-gamma and picolinic acid. Although IL-4 inhibited the expression of IFN-gamma plus picolinic acid-induced TNF-alpha mRNA and protein, it only partially suppressed picolinic acid-dependent NO2- production. Therefore, picolinic acid may affect NO2- production via both TNF-alpha-dependent and TNF-alpha-independent pathways. Overall, this study suggests that amino acid catabolites may be important for the activation and the expression of effector functions by murine macrophages, and provides the first evidence of a possible connection between tryptophan and arginine metabolism.

Animals↗