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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↗

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↗

PubMedDate not supplied

Effect of chromium picolinate on histopathological alterations in STZ and neonatal STZ diabetic rats.

Earlier studies from our laboratory have indicated insulin sensitizing action of chromium picolinate as the mechanism of its anti-diabetic activity in experimental models of type I and type II diabetes. In the present investigation, we have evaluated the effects of chronic administration of chromium picolinate on the functional and histological alterations of streptozotocin (STZ)-induced diabetes in rats. Type I diabetes was induced by intravenous injection of STZ (40 mg/kg) in adult rats, whereas, type II diabetes was induced by intraperitoneal injection of STZ (90 mg/kg) in 2-day old rat pups which in adulthood develop abnormalities resembling type II diabetes. Chromium picolinate was administered at 8 microg/ml in drinking water for 6 weeks and was found to improve glucose tolerance and increase insulin sensitivity of STZ-diabetic rats. This treatment decrease elevated serum creatinine and urea levels as well as elevated serum levels of hepatic enzymes of both groups of diabetic rats. Histopathological studies of kidney and liver show decrease in the intensity and incidence of vacuolations, cellular infiltration and hypertrophy of STZ and nSTZ (neonatal STZ) diabetic rats. Chronic treatment with chromium picolinate however, did not alter the normal function or morphology of control rats. Chronic chromium picolinate at the therapeutic doses that improved glucose tolerance, was observed to have no hepatotoxic or nephrotoxic potential. It was rather found to improve renal and hepatic function and to reduce abnormalities associated with STZ-diabetes. Chromium picolinate could play an important role in the long term management of diabetes mellitus.

Animals↗

PubMed2001

Laboratory evolution of toluene dioxygenase to accept 4-picoline as a substrate.

We are using directed evolution to extend the range of dioxygenase-catalyzed biotransformations to include substrates that are either poorly accepted or not accepted at all by the naturally occurring enzymes. Here we report on the oxidation of a heterocyclic substrate, 4-picoline, by toluene dioxygenase (TDO) and improvement of the enzyme's activity by laboratory evolution. The biotransformation of 4-picoline proceeds at only approximately 4.5% of the rate of the natural reaction on toluene. Random mutagenesis, saturation mutagenesis, and screening directly for product formation using a modified Gibbs assay generated mutant TDO 3-B38, in which the wild-type stop codon was replaced with a codon encoding threonine. Escherichia coli-expressed TDO 3-B38 exhibited 5.6 times higher activity toward 4-picoline and approximately 20% more activity towards toluene than wild-type TDO. The product of the biotransformation of 4-picoline is 3-hydroxy-4-picoline; no cis-diols of 4-picoline were observed.

Amino Acid Sequence↗

PubMed1990

The effect of chromium picolinate on serum cholesterol and apolipoprotein fractions in human subjects.

Chromium has been implicated as a cofactor in the maintenance of normal lipid and carbohydrate metabolism. A deficiency of chromium results from diets low in biologically available chromium. Picolinic acid, a metabolite of tryptophan, forms stable complexes with transitional metal ions, which results in an improved bioavailability of the metal ion chromium. To determine whether or not chromium picolinate is effective in humans, 28 volunteer subjects were given either chromium tripicolinate (3.8 micromol [200 micrograms] chromium) or a placebo daily for 42 days in a double-blind crossover study. A 14-day period off capsules was used between treatments. Levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B, the principal protein of the LDL fraction, decreased significantly while the subjects were ingesting chromium picolinate. The concentration of apolipoprotein A-I, the principal protein of the high-density lipoprotein (HDL) fraction, increased substantially during treatment with chromium picolinate. The HDL-cholesterol level was elevated slightly but not significantly during ingestion of chromium picolinate. Only apolipoprotein B, of the variables measured, was altered significantly during supplementation with the placebo. These observations show that chromium picolinate is efficacious in lowering blood lipids in humans.

Adult↗

PubMed1995

Chromium(III) picolinate produces chromosome damage in Chinese hamster ovary cells.

Chromium(III) complexes currently being sold as dietary supplements were tested for their ability to cause chromosomal aberrations in Chinese hamster ovary cells. Complexes were tested in soluble and particulate forms. Chromium picolinate was found to produce chromosome damage 3-fold to 18-fold above control levels for soluble doses of 0.050, 0.10, 0.50, and 1.0 mM after 24 h treatment. Particulate chromium picolinate doses of 8.0 micrograms/cm2 (corresponding to a 0.10 mM solublized dose) and 40 micrograms/cm2 (0.50 mM) produced aberrations 4-fold and 16-fold above control levels, respectively. Toxicity was measured as a decrease in plating efficiency relative to controls. The above treatments produced > or = 86% survival for all doses except 1.0 mM chromium picolinate, which produced 69 +/- 10% survival. Chromium nicotinate, nicotinic acid, and chromium(III) chloride hexahydrate did not produce chromosome damage at equivalent nontoxic doses. Damage was inferred to be caused by the picolinate ligand because picolinic acid in the absence of chromium was clastogenic. Data are evaluated in terms of their relevance to human exposure based on pharmacokinetic modeling of tissue accumulation and are discussed in terms of literature reporting toxic effects of picolinic acid.

Animals↗

PubMed1996

Chromium picolinate.

Chromium picolinate is a dietary supplement gaining in popularity among Americans, especially those seeking a weight-reduction program. Although the mechanism(s) responsible for the purported actions of chromium picolinate have not been thoroughly investigated, studies suggest that the biochemical, physiological, and behavioral actions of chromium picolinate may be a consequence of the effects of picolinic acid on the central nervous system. Analogues of picolinic acid have been shown to induce profound alterations in the metabolism of serotonin, dopamine, and norepnephrine in brain. Thus, caution should be used with chromium picolinate supplements especially by individuals prone to behavioral disorders.

Adult↗

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↗

PubMed2002

Ultrastructural damage in chromium picolinate-treated cells: a TEM study. Transmission electron microscopy.

Chromium picolinate (CrPic) is a human dietary supplement that provides a bioavailable form of chromium(III). Its mechanism of action is unknown, and a number of toxic endpoints have been attributed to its use. Understanding the cellular effects of CrPic is important for confirmation or dismissal of these potential toxic effects. The purpose of this work was to characterize morphological damage caused by CrPic, picolinic acid, and chromic chloride in Chinese hamster ovary AA8 cells. A 48-h exposure to 80 micro g/cm(2) CrPic (0.44 mg/mL CrPic) produced 45% survival by colony formation. Transmission electron microscopy (TEM) showed 83% of analyzed cells having swollen mitochondria with degraded cristae. Apoptosis was identified by nuclear convolution and fragmentation, and cytoplasmic blebbing. Apoptosis was quantified by fluorescence microscopy with acridine orange/ethidium bromide staining. At the 80 micro g/cm(2) dose of CrPic, 37% of the cells were apoptotic cells at 48 h. An equivalent dose of picolinate, 3 mM, was much more cytotoxic and thus there was an inadequate cell number for TEM analysis. However, a lower dose of 1.5 mM induced 49% cell survival, and damaged 86% of the mitochondria, with 51% of the cells undergoing apoptosis. A dose of 1 mM chromic chloride produced 71% cell survival, and damaged 86% of the mitochondria, with 22% of the cells undergoing apoptosis. The amount of apoptosis correlated with overall cell survival by colony formation, but not with the amount of mitochondrial damage. The coordination of Cr(III) by picolinate ligands may alter the cellular chemistry of Cr(III) to make chromium picolinate a toxic form of Cr(III).

Animals↗

PubMed1992

Chromium picolinate increases membrane fluidity and rate of insulin internalization.

The effects of chromium chloride, chromium nicotinate, and chromium picolinate on insulin internalization in cultured rat skeletal muscle cells was examined. Insulin internalization was markedly increased in cells cultured in a medium that contained chromium picolinate and the increased internalization rate was accompanied by a marked increase in the uptake of both glucose and leucine. The effect was specific for chromium picolinate since neither zinc picolinate nor any of the other forms of chromium tested was effective. The increased insulin internalization rate may result from an increase in membrane fluidity since chromium picolinate and to a lesser extent, chromium nicotinate, increased the membrane fluidity of synthetic liposomal membranes.

Animals↗

PubMed1997

Picolinic acid and indole-2-carboxylic acid: two types of glycinergic compounds modulate motor function differentially.

1. A putative agonist for the strychnine-sensitive glycine receptor picolinic acid was tested for its anticonvulsant activities in mice and muscle-relaxant activities in rats and compared with indole-2-carboxylic acid (I2CA), an antagonist for the strychnine-insensitive glycine receptor. Their effects on segmental reflexes in the cat spinal cord were examined to elucidate their sites of action. 2. Picolinic acid (200 and 400 mg/kg IP) delayed the onsets of strychnine- but not pentylenetetrazole-induced seizures. It delayed the onsets of bicuculline-induced seizures only at the higher dose. I2CA (200 and 400 mg/kg IP) delayed the onsets of these 3 kinds of seizures. Both compounds reduced muscle tone in rat decerebrate rigidity at a dose of 100 mg/kg IV. 3. Picolinate methylester, a picolinate derivative with higher lipophilicity, depressed spinal reflexes in both intact and spinalized cats at cumulative doses of 25 to 200 mg/kg IV. I2CA (50 mg/kg IV) inhibited spinal reflexes only in intact preparations. 4. These results suggest that the anticonvulsant and muscle-relaxant activities of picolinic acid (PA) are due to inhibition of spinal neurons, but that I2CA selectively affects supraspinal structures.

Animals↗

PubMed2001

New high-performance liquid chromatographic method for the detection of picolinic acid in biological fluids.

A HPLC method is described to quantify picolinic acid in milk, blood serum and tissue culture supernatant. The method requires very little sample preparation because acid precipitation allows total recovery of picolinic acid. High specificity and sensitivity were obtained using ion-pair chromatography on a C18 reversed-phase column with tetrabutylammonium hydrogen sulfate as ion pairing reagent. We describe the conditions for the automated testing of multiple samples and for the detection of L-tryptophan and L-kynurenine together with picolinic acid. This system will be utilized to elucidate the relationship between picolinic acid production and human disease. Furthermore, we provide the first evidence of picolinic acid in human blood serum.

Animals↗

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↗

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↗

PubMed1977

Study of inhibition of outgrowth in Bacillus cereus T by ethyl picolinate.

The effects of ethyl picolinate on germination, outgrowth, and sporulation of Bacillus cereus T were studied in a synthetic medium containing glucose. Ethyl picolinate specifically inhibited at two stages, outgrowth and sporulation. The initiation of germination and cell division was not affected. The inhibition of outgrowth by ethyl picolinate could be reversed by enrichment of inoculum with aspartic acid, asparagine, lysine, phenylalanine, and tyrosine among the amino acids and by oxalacetate. Nicotinic acid and nicotinamide also possessed this ability. Ethyl picolinate failed to block outgrowth when added to cultures incubated for a short time after inoculation. Enrichment of the medium with lysine plus zinc sulfate stimulated sporulation in the presence of ethyl picolinate to a significance degree.

Amino Acids↗

PubMed1989

Anti-coccidial activity of 2-picoline, 6-amino-4-nitro-, 1-oxide.

An investigational drug (2-picoline, 6-amino-4-nitro-, 1-oxide) was evaluated to characterize the anti-coccidial spectrum of the compound. Two concentrations of the drug (125 and 250 ppm) were evaluated for bioactivity; weight gain, survival, dropping, and lesion scores were the response variables utilized to ascertain activity. The activities of the picoline derivative were compared with monensin, maduramicin, and a narasin/nicarbazin (1:1) combination. The investigational drug had significant activity against Eimeria tenella and Eimeria necatrix, and the 250-ppm level was significantly more active than 125 ppm. At 250 ppm, the E. tenella activity of the picoline derivative was comparable to both monensin (120 ppm) and the 50-ppm narasin/nicarbazin combination, significantly less effective than maduramicin (6 ppm), and significantly more efficacious than 30 ppm narasin/nicarbazin. At the same level (250 ppm), the picoline derivative had significantly less E. necatrix activity than monensin (120 ppm), maduramicin (6 ppm), and narasin/nicarbazin (50 ppm), and significantly greater activity than 30 ppm narasin/nicarbazin. At best, only extremely weak Eimeria acervulina, Eimeria brunetti, and Eimeria maxima activities were noted with the investigational drug; higher concentrations of the picoline derivative may achieve greater anti-coccidial activity against these species. The efficacy of narasin/nicarbazin compared favorably with monensin and maduramicin; the 50-ppm level of the combination appeared significantly more efficacious than 30-ppm.

Animals↗

PubMed1974

Microbial Decomposition of alpha-Picoline.

An organism, which degrades alpha-picoline but also utilizes 2-ethylpyridine or piperidine as alternative growth substrates, has been isolated from soil and characterized as arthrobacter sp. alpha-picoline-grown cells oxidize 2-ethylpyridine and vice versa. Other pyridine derivatives tested are neither utilized as growth substrates nor oxidized by the organism. alpha-Picolinate and 2-hydroxy-6-methylpyridine are not metabolized, indicating that degradation is neither initiated by methyl oxidation nor by hydroxylation in the 6-position of pyridine ring. Succinate semi-aldehyde and pyruvate accumulate when alpha-picoline oxidation by resting cell suspensions is blocked by semicarbazide. The Arthrobacter grown on alpha-picoline rapidly oxidizes succinate semi aldehyde...

Arthrobacter↗