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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↗
PubMedDate not supplied

Antiviral, cytotoxic and apoptotic activities of picolinic acid on human immunodeficiency virus-1 and human herpes simplex virus-2 infected cells.

The antiviral, cytotoxic and apoptotic effects of picolinic acid against human immunodeficiency virus-1 (HIV-1) and human herpes simplex virus-2 (HSV-2) infected cells were evaluated in cultured cells using in vitro assays. Picolinic acid was tested at several concentrations (from 0.15 to 3 mM) against one input dilution of the viruses to determine if the agent had any antiviral activity against HIV-1 or HSV-2. The results showed that picolinic acid at 1.5 mM (185 ug/mL) and 3 mM (369 ug/mL) was active against HIV-1 and HSV-2-infected cells, causing cytotoxicity which resulted in apoptosis and lack of viral replication. In parallel control experiments with non-infected cells, picolinic acid also caused cytotoxicity and apoptosis, which was more prominent at 3 mM than at 1.5 mM. Thus, infected cells appear to be slightly more sensitive to the cytotoxic and apoptotic effects of picolinic acid. The overlapping of the antiviral profile with the cytotoxic profile of picolinic acid indicates that, in vitro, the most likely sequence of events is that picolinic acid initially causes cytotoxicity which in turn results in apoptosis of cells infected with HIV-1 or HSV-2 and thus reduces the amount of viral replication.

Anti-HIV Agents↗
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↗
PubMed1982

The influence of intraruminal and intraduodenal infusion of picolinic acid on metabolism of 65Zn in sheep.

Two experiments with sheep were carried out to study the influence of picolinic acid on zinc metabolism. In the first experiment, sheep were infused with water into the duodenum and with picolinic acid into the rumen or duodenum. All the sheep were then intraduodenally dosed with 65Zn. In the second experiment, sheep were intraduodenally infused with water or picolinic acid and then intravenously dosed with 65Zn. Necessary sampling of urine, faeces, blood or digesta were carried out in both experiments. The infusion with picolinic acid did not affect the faecal excretion or endogenous secretion of 65Zn but increased the urinary excretion of the radioisotope and ruminal solubility of zinc. However, te duodenal and ileal solubilities of zinc were not affected by the treatment. It was concluded that an exogenous supplement of picolinic acid is not effective in promoting higher absorption of zinc in ruminant animals.

Animals↗
PubMed1978

Iron transport in NRK cells synchronized in G(1) by picolinic acid.

NRK cells treated with picolinic acid are arrested in G(1)(G0). After removal of the agent a wave of transferrin-dependent iron uptake was observed only in early G(1). Therefore, iron transport is a primary event in the reinitiation of cell growth and may be connected with subsequent metabolic steps leading to initiation of DNA synthesis.

Animals↗
PubMed2002

Drug targeting to the brain: transfer of picolinic acid along the olfactory pathways.

Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [3H]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [3H]PA. After 4 h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [3H]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [3H]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.

Administration, Intranasal↗
PubMed1983

[Influence of picolinic acid and citric acid on intestinal absorption of zinc in vitro and in vivo].

The influence of the ligands picolinic acid and citric acid on the intestinal absorption of zinc was studied in two different experimental trials with Zn-depleted and Zn-supplied pair-fed rats using everted sacs in vitro and the ligated small intestine in vivo. ZnSO4 was applied in water solution (pH 5.8) without ligands or together with picolinic acid at a molar ratio of 1:0.2, 1:2, and 1:20 or together with citric acid at a molar ratio of 1:1, 1:10, and 1:100. The intestinal Zn transfer of the Zn-depleted rats with picolinic acid is significantly increased only at a molar ratio of 1:20 (zinc:ligand) (P less than 0.001). The other in vitro results of Zn absorption were only slightly improved, mainly at the high molar excess of picolinic acid in comparison to ZnSO4 without ligands. Only a tendency for an increased Zn transfer--however, already at a narrow molar ratio of 1:1 or 1:10--could be seen when citric acid was added. The intestinal uptake was not influenced by citric acid. The absorption of zinc in vivo did not vary in dependence of the addition of picolinic or citric acid in different molar ratio in comparison to ZnSO4 addition without ligands. Zn-depleted rats showed a significantly higher Zn absorption rate than Zn supplied pair-fed rats independently of the kind of ligand and the zinc:ligand ratio (P less than 0.001). These results are discussed in detail.

Animals↗
PubMed1980

Zinc absorption in rats fed a low-protein diet and a low-protein diet supplemented with tryptophan or picolinic acid.

Zinc absorption was examined in rats fed a basal diet with 5% vitamin-free casein, in rats fed the 5% casein-based diet supplemented with tryptophan and in rats fed the 5% casein-based diet supplemented with picolinic acid. True, total daily zinc absorption was determined by an isotope dilution technique after the rats had been injected intramuscularly with carrier-free 65Zn. The zinc concentration of the kidneys from the rats fed the 5% casein diet was significantly less than that of the kidneys from rats fed the same diet supplemented with either tryptophan or picolinic acid. The specific activity of Zn in the kidneys from the rats fed the low-protein diet was significantly greater than that of the kidneys from rats fed the diet supplemented with either tryptophan or picolinic acid. The specific activity of Zn in the feces from rats fed the low-protein diet was significantly less than the specific activity of the feces from rats fed either supplemental tryptophan or supplemental picolinic acid. True, total daily zinc absorption in rats fed the low-protein diet was significantly less than the total daily zinc absorption in rats fed either supplemental tryptophan or supplemental picolinic acid. Since tryptophan is a metabolic precursor of picolinic acid, the results support the hypothesis that endogenous and exogenous picolinic acid facilitates zinc absorption.

Absorption↗
PubMed1990

Is picolinic acid a glycine agonist at strychnine-sensitive receptors?

By means of unit recording and electrophoretic application, the effect of picolinic acid on feline spinal interneurons in situ was studied in comparison with glycine. Picolinic acid inhibited neuronal firing in 60% of neurons and in some cases the inhibitory actions were antagonized by strychnine. Inhibition of firing by glycine, which was also strychnine-sensitive, was reduced in case of concomitant administration of picolinic acid. These results suggest that picolinic acid might act as a glycine agonist at strychnine-sensitive receptors.

Animals↗
PubMedDate not supplied

[Structure-physiological activity correlation for picolinic acid derivatives based on quantum chemical data].

Correlation between structure and properties for picolinic acid derivatives with and without bimodal effect was evaluated by quantum chemical calculations. Comparative data obtained by SCF MO method in the 3-21G/6-31G* basis indicate lower ionization potential in picolinic acid derivatives with bimodal effect as compared to those lacking this effect. This validates our previous assumption that physiological bimodal effect is defined by the electron structure of the molecules. Quantum chemical calculations allowed us to predict bimodal physiological activity in amino-substituted derivatives of picolinic acid.

Molecular Structure↗
PubMed1985

Effect of dietary picolinic acid on the metabolism of exogenous and endogenous zinc in the rat.

The excretion of 65Zn was compared by metabolic balance studies in adult male rats fed purified diets containing 0.8 mmol Zn/kg diet, with and without 40 mmol picolinic acid per kilogram diet, after single intragastric (i.g.) and intraperitoneal (i.p.) doses of the isotope. In a third experiment picolinic acid was introduced for 3 d into the diet of rats prelabeled with 65Zn. The urinary excretion of total zinc was increased by the ingestion of picolinic acid in all three experiments. The urinary and fecal outputs of 65Zn were both consistently greater in picolinic acid-fed rats than in the corresponding control animals. This was particularly marked after i.p. injection of the tracer, and the specific activities of urine and feces from the treated rats were both increased. When picolinic acid was introduced into the diet of prelabeled rats there was a delay of 24 h in the urinary response and 48 h in the fecal response. The residual 65Zn levels were reduced in several tissues from the picolinic acid-fed rats, especially after i.p. administration of the isotope. These observations indicate that dietary picolinic acid increases the turnover of endogenous zinc in addition to enhancing the absorption and excretion of ingested metal, and this has implications for its use in cases of zinc deficiency.

Absorption↗
PubMed1995

Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell subclone HT29-18-C1.

A lactoferrin receptor has been found on the brush-border membrane of intestinal epithelial cells of several species, including humans. A role for this receptor in intestinal iron absorption, which is well regulated in response to body iron stores, has been proposed. We have investigated the effect of intracellular iron depletion by picolinic acid, an iron chelator, on the cell surface binding of human lactoferrin to human enterocytes and its intracellular uptake, using HT29-18-C1 cells, an enterocyte-like differentiable cell line. The confluent cells exhibited 5.8 x 10(6) specific binding sites per cell for diferric human 125I-labelled lactoferrin with relatively low affinity (Kd 8.4 x 10(-7) M). The addition of picolinic acid to the culture medium resulted in a concentration- and time-dependent increase in lactoferrin binding that was correlated with a decrease in intracellular iron content. The maximum effect of picolinic acid on lactoferrin binding (approx. 2-fold increase), which appeared between 12 and 18 h after its addition, was obtained at a picolinic acid concentration of 2 mM. Scatchard analysis showed that the enhanced lactoferrin binding resulted from an increase in the number of lactoferrin receptors rather than an alteration in the binding affinity for lactoferrin. The time-dependent effect of picolinic acid was completely abolished in the presence of 1 microM anisomycin, a protein synthesis inhibitor, indicating that ongoing protein synthesis is involved in this effect. The enhanced lactoferrin binding induced by picolinic acid produced an increase of approx. 30% in the uptake of lactoferrin-bound 59Fe, indicating the existence of functional receptors. These results suggest that biosynthesis of lactoferrin receptors in intestinal epithelial cells can be regulated in response to the levels of intracellular chelatable iron, consistent with intestinal iron absorption dependent on body iron stores.

Biological Transport↗
PubMed1981

Effect of iron, vitamin B-6 and picolinic acid on zinc absorption in the rat.

True daily zinc absorption was determined in rats fed a high iron diet (220 ppm Fe; 16.5 ppm Zn), and adequate iron diet (30 ppm Fe) and a high iron diet with varying levels of pyridoxine-HCl (2-40 ppm). Zinc absorption in rats fed the high iron diet was significantly less than in rats fed the adequate iron diet. Zinc absorption in rats fed the high iron diet supplemented with picolinic acid (200 ppm) was markedly increased and did not differ from that in rats fed the adequate iron diet. True, daily zinc absorption increased as the level of dietary vitamin B-6 was increased. Zinc absorption was the least in rats fed 2 ppm vitamin B-6 and was greatest in rats fed 40 ppm vitamin B-6. The concentration of picolinic acid in the pancreas increased as the level of dietary vitamin B-6 was increased. Zinc absorption was significantly elevated in rats fed the high iron diet that contained either 4 or 10 ppm vitamin B-6 and 200 ppm picolinic acid. The turnover rate of 65Zn was determined in rats fed an adequate iron, marginal zinc diet (8.5 ppm Zn) with varying levels of vitamin B-6. The turnover of 65Zn was greatest in rats fed 2 ppm vitamin B-6 and least in rats fed 40 ppm vitamin B-6 or 2 ppm vitamin B-6 + 200 ppm picolinic acid. The results suggest that high levels of dietary iron inhibit zinc absorption via competition for binding with endogenous picolinic acid. The results provide further evidence to support the hypothesis that picolinic acid facilitates absorption of dietary zinc.

Absorption↗
PubMed1981

Cell cycle kinetics of Chinese hamster (CHO) cells treated with the iron-chelating agent picolinic acid.

Spontaneously transformed (tumorigenic) Chinese hamster cells (line CHO) do not exhibit picolinic acid-sensitive G1 and G2 cell cycle arrest points observed in normal and virus-transformed cells. Rather, picolinic acid arrests CHO cells in S phase only and produces culture growth behaviour similar to that produced by hydroxyurea. Prolonged treatment with picolinic acid permits a slow but significant traverse of cells through S phase. Thus, like hydroxyurea, picolinic acid is not a useful agent for synchronizing exponential CHO cells, but it can be used to resynchronize cultures in early S phase if a previous synchronization procedure (such as isoleucine deprivation) is used. The iron chelating properties of picolinic acid, and the similarities of its effects on cultured cells to those of hydroxyurea and the iron-chelating drug desferrioxamine, suggest that picolinic acid inhibits DNA synthesis by interfering with the iron-dependent production of a stable free organic radical which is essential for the ribonucleotide reductase formation of deoxyribonucleotides.

Animals↗