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PubMed1999

Diethanolamine inhibits choline uptake and phosphatidylcholine synthesis in Chinese hamster ovary cells.

Diethanolamine (DEA), an alkanolamine used widely in industry, is hepatocarcinogenic in mice. The goal of this work was to determine whether DEA altered choline homeostasis in cultured cells, so as to ascertain whether the liver tumor response may be related to choline deficiency. CHO cells were cultured in Ham's F-12 medium containing DEA (0-1000 microgram/ml) and [(33)P]-phosphorus was used to label phospholipid pools. After 48 hours incubation, lipids were extracted and [(33)P]-labeled phospholipids were quantified by autoradiography after thin layer chromatographic separation. In control cells, phosphatidylcholine (PC) accounted for 51 +/- 0.7% of the total lipid (33)P incorporation. DEA had no effect on cell number or total phospholipid biosynthesis, but it significantly decreased the incorporation of (33)P into PC at concentrations >/=50 microgram/ml. DEA (>/=20 microgram/ml) also inhibited the uptake of [(3)H]-choline into CHO cells, with 95% inhibition observed at 250 microgram/ml. To determine whether supplemental choline prevented PC synthesis inhibition by DEA, CHO cells were cultured with or without excess choline (30 mM) and DEA (500 microgram/ml). DEA reduced PC synthesis to 27 +/- 3% of total phospholipids, but had no effect on PC synthesis in choline-supplemented cells. When [(14)C]-DEA was incubated with CHO cells, it was also incorporated into the phospholipid fraction. Collectively, these results indicate that DEA reversibly inhibits PC synthesis by blocking choline uptake and competing for utilization in the CDP-choline pathway in CHO cells.

Animals↗
PubMed1983

Induction of acid phosphatase and cholinesterase activities in Ps. aeruginosa and their in-vitro control by choline, acetylcholine and betaine.

Choline, acetylcholine and betaine used as a sole carbon source, effectuate in Ps. aeruginosa an acid phosphatase activity in addition to a cholinesterase activity. Induction of both enzyme activities was repressed by succinate or glucose. Cyclic AMP failed to relieve the repression produced by these compounds. Substrates not related to choline and used as a sole source of carbon, were inefficient to produce induction of both enzymes. The in-vitro action of choline, acetylcholine and betaine on Ps. aeruginosa acid phosphatase and cholinesterase has also been studied. To perform these studies periplasmic extracts obtained by EDTA-lysozyme treatment of the cells grown on choline or betaine as sole source of carbon, were used. Acid phosphatase activity was competitively inhibited by betaine, whereas the inhibition produced by choline and acetylcholine showed competitive and noncompetitive components. Cholinesterase activity was noncompetitively inhibited by betaine. At low acetylthiocholine concentration choline was an inhibitor of cholinesterase, whereas at high substrate concentration choline raised the hydrolysis rate of acetylthiocholine. These findings allow the conclusion that acid phosphatase and cholinesterase are specifically induced by choline and its metabolites derivatives. Kinetic results led us to postulate that acid phosphatase and cholinesterase contain a similar allosteric site. This site would either be of an anionic nature or show affinity to a methyl group or display both characteristics.

Acetylcholine↗
PubMed1977

Inhibition of choline incorporation into brain lipids in rats by urethane, a proposed mechanism of depression of the central nervous system.

Concentrations and specific radioactivities of choline, acetylcholine, phosphorylcholine, lipid choline, and sn-glycero-3-phosphorylcholine after i.v. injection of methyl-14C-choline were measured in the brain of untreated controls and of rats anesthesized with urethane. The specific activity was found to be decreased during deep anesthesia by 40% in acetylcholine, 20-30% in phosphorylcholine, 50-75% in lipid choline, and 30-40% in sn-glycero-3-phosphoryl-choline. No significant change was detected in the specific activity of choline. The brain concentration of acetylcholine was increased by 40%, the concentration of sn-glycero-3-phosphorylcholine, however, was diminished by 10% during anesthesia. No change was found in the concentration of the other choline containing compounds investigated. Measuring choline incorporation into 4 subcellular fractions of brain tissue specific activities were found to be decreased by the same percentage, although 2 fractions (nuclei and microsomes) were higher labelled than the 2 other fractions (crude mitochondria with synaptosomes and lysosomes). A correlation between the biochemical and the functional alterations is supported by the dose-effect relationships on both parameters. It is suggested that urethane reduces turnover of lipids and by that mechanism inhibits the exocytotic release of the transmitter from presynaptic nerve endings.

Animals↗
PubMed1986

The release of choline from phospholipids mediated by beta-adrenoceptor activation in isolated hearts.

The resting efflux of choline into the perfusate (Tyrode's solution) of isolated hearts was equal to the rate, at which choline was liberated from phospholipid degradation (Lindmar et al. 1986). Infusion of isoprenaline (2 X 10(-7) mol/l), forskolin (1-3 X 10(-6) mol/l) or 3-isobutyl-1-methylxanthine (IBMX; 3 X 10(-4) mol/l) for 40 min markedly enhanced the efflux of choline. The increase was linear during the experimental period and, in the case of isoprenaline, was blocked by 3 X 10(-7) mol/l atenolol. In the guinea-pig heart, IBMX at a threshold concentration of 10(-4) mol/l shifted the concentration-response curve for the effect of forskolin on the efflux of choline to the left by one log unit. Forskolin (10(-6) mol/l) increased also the tissue content of cyclic AMP. This effect and the increase of choline efflux evoked by forskolin were blocked by 2 X 10(-7) mol/l carbachol. Likewise, inhibition of cholinesterase activity caused by diisopropylfluorophosphate antagonized the forskolin-evoked acceleration of choline efflux indicating a response to endogenous acetylcholine. The muscarinic inhibition of the enhanced choline efflux was reversed by 3 X 10(-7) mol/l atropine. The phospholipase A2 inhibitor mepacrine as well as infusion of a low Ca2+-Tyrode's solution (0.2 instead of 1.8 mmol/l) blocked the effect of forskolin on choline efflux, whereas the generation of cyclic AMP by forskolin was unaffected by low Ca2+-solution.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1985

Choline fluxes in synaptosomal membrane vesicles.

Synaptic plasma membrane vesicles isolated from the highly cholinergic nervous tissue of insects were used to study the translocation of choline across the membrane via a high-affinity carrier-mediated mechanism energized by ion gradients as the sole driving force. The uphill movement of choline, energized mainly by the Na+ gradient, attained levels of choline severalfold the final equilibrium value at the peak of the overshoot. Efflux of choline required the presence of internal sodium ions and was promoted by external choline if Na+ was present. External choline inhibited choline efflux in the absence of sodium. It is concluded that the efflux of choline is in many aspects symmetrical with its uptake.

Animals↗
PubMed1982

Possible role of sialocompounds in the uptake of choline into synaptosomes and nerve cell cultures.

Incubation of primary nerve cell cultures and of crude synaptosomal preparations with neuraminidase released sialic acid from both gangliosides and sialoglycoproteins. After this treatment, the pattern of ganglioside distribution was severely modified with a decrease of polysialogangliosides (GD1b, GT1b, Gt1L, GQ1) and a dramatic increase in monosialoganglioside GM1. The choline influx into neuraminidase treated cells and organelles was reduced by 30--50% but the efflux was unmodified. In particular the high affinity mechanism of choline uptake disappeared and the low affinity mechanism was modified in both cases. The disappearance of the high affinity uptake mechanism was not followed by a decreased acetylcholine synthesis as it should be if the current theories on choline uptake and acetylcholine synthesis are correct. Our present data thus confirm our previous hypothesis that choline metabolism regulates choline uptake rather than the other way round as is suggested by the theories most widely accepted at present. Choline uptake was unaffected by pretreatment of cells and organelles with tetanus toxin suggesting that the effect of neuraminidase on the choline uptake were either mediated through glycoproteins or through gangliosides other than those which bind to tetanus toxin (GD1b and GT1b). Several speculative models for explaining the effect of neuraminidase on choline uptake are proposed.

Animals↗
PubMed1995

Ultrastructural identification of cholinergic neurons in the external cuneate nucleus of the gerbil: acetylcholinesterase histochemistry and choline acetyltransferase immunocytochemistry.

Using acetylcholinesterase histochemical and choline acetyltransferase immunocytochemical localization methods, this study has provided conclusive evidence for the existence of cholinergic neurons in the external cuneate nucleus of gerbils. By light microscopy, both acetylcholinesterase and choline acetyltransferase labelling was confined to the rostral portion of the external cuneate nucleus. Ultrastructurally, acetylcholinesterase reaction products were found in the nuclear envelope, cisternae of rough endoplasmic reticulum and Golgi saccules of some somata and large dendrites as well as in the membranes of small dendrites, myelinated axons and axon terminals. These neuronal elements were also stained for choline acetyltransferase; immunoreactivity was associated with nuclear pores, nuclear envelope, perikaryal membrane and all the membranous structures within the cytoplasm. Of the total choline acetyltransferase-labelled neuronal profiles analysed, 79% were myelinated axons, 15% dendrites, 4% somata and 2% axon terminals. The immunostained axon terminals consisted of two types containing either round (Rd type; 62.5%) or pleomorphic (Pd type; 37.5%) vesicles. Both were associated directly with choline acetyltransferase-positive dendrites. In contrast to the paucity of choline acetyltransferase-labelled axon terminals, numerous choline acetyltransferase-positive myelinated axons were present. It may thus be hypothesized that most, if not all, of the external cuneate nucleus cholinergic neurons are projection cells; such cells may give rise to axonal collaterals which synapse onto their own dendrites for possible feedback control. Choline acetyltransferase-positive dendrites were contacted by numerous unlabelled presynaptic boutons, 60% of which contained round or spherical synaptic vesicles (Rd boutons) and 40% flattened vesicles (Fd boutons), suggesting that these neurons are under strong inhibitory control. The preferential concentration of cholinergic components in the rostral external cuneate nucleus may be significant in the light of the highly organized somatotopy in the external cuneate nucleus and its extensive efferent projections to medullary autonomic-related nuclei. Our results suggest that the cholinergic neurons may be involved in somatoautonomic integration.

Acetylcholinesterase↗
PubMed1995

Radioactive choline metabolism in guinea pig gallbladder. Is there measurable acetylcholine release?

Acetylcholine may be released from gallbladder intrinsic nerves in response to cholecystokinin stimulation. This study characterized metabolites of [14C]choline produced in the gallbladder and released during incubation, with or without cholecystokinin-octapeptide. Radiolabeled [14C]choline was applied to the mucosal or muscle surface of intact guinea pig gallbladders in an organ bath. After radiolabeling, gallbladders were incubated with or without the contractile agonist cholecystokinin-octapeptide. Metabolites of [14C]choline were identified in gallbladder tissue and incubation buffers using HPLC and thin-layer chromatography. The major metabolites of [14C]choline were betaine and phosphocholine. [14C]Phosphocholine was incorporated slowly into [14C]phosphatidylcholine. [14C]Choline was released into buffers during incubation. [14C]Acetylcholine constituted less than 1% of radiolabel in the gallbladder. There was no identifiable [14C]acetylcholine released in buffers. Cholecystokinin-octapeptide did not affect choline metabolism. These studies showed that choline in the gallbladder is metabolized along pathways similar to those in the liver. Gallbladders released mostly choline, rather than acetylcholine, even during hormonally induced contraction.

Acetylcholine↗
PubMed1979

Ethanolamine kinase activity and compositions of diacylglycerols, phosphatidylcholines and phosphatidylethanolamines in livers of choline-deficient rats.

These experiments were performed to find the reasons for the increased concentrations of docosahexaenoyl phosphatidylethanolamines (PE) in livers of choline-deficient rats. We measured the activity of ethanolamine kinase, which catalyzes the first step in PE formation. We also measured the compositions of PE and phosphatidylcholines (PC) and concentrations and fatty acid compositions of diacylglycerols (DG), which are precursors of PE. Young male rats were fed for one week a low-methionine, choline-deficient diet, or the same diet supplemented with choline. Ethanolamine kinase activity was measured in liver cytosol (100,000 g supernatant). Fatty acids were measured in total liver diacylglycerols and in microsomal PE and PC. Ethanolamine kinase activities were equal in choline-deficient and choline-supplemented rats. Concentrations of DG were elevated 6-fold by choline deficiency. The percentage of docosahexaenoic acid (22:6n-3) in microsomal PE was nearly doubled by choline deficiency. Although the increased concentrations of PE in choline-deficient livers cannot be attributed to increased activity of ethanolamine kinase, the rate of PE formation probably was increased by increases in concentrations of its precursors, including DG. The disproportionate increase in 22:6n-3 PE probably was caused by a selective formation of PE from DG that contain 22:6n-3.

Animals↗
PubMed1979

Determination of free choline and phosphorylcholine in rat liver.

A simple procedure for determination of levels of free choline and phosphorylcholine in hepatic tissue is outlined. The method makes use of the enzyme acid phosphatase to liberate choline from phosphorylcholine and incorporates the ability of choline to react with potassium triiodide to yield choline periodide for the measurement of choline and phosphorylcholine in liver. The method is accurate for both entities (recovery of 97-100% for choline and 92-98% for phosphorylcholine). For phosphorylcholine, the method is markedly simpler than other methods previously described and the results for normally fed rats are of the same order of magnitude. The applicability of the method was shown when it was demonstrated that diets containing different amounts of choline influenced the level of choline and phosphorylcholine in liver.

Animals↗
PubMed1992

The effect of amino acids on choline uptake and phosphatidylcholine biosynthesis in mammalian hearts.

The uptake of choline in mammalian hearts in the presence of amino acids was examined. Isolated hamster, guinea pig, rat and rabbit hearts were perfused with labeled choline in the presence and absence of amino acids. Neutral amino acids enhanced choline uptake in the hamster heart, but not in the guinea pig, rat and rabbit hearts. Phosphatidylcholine biosynthesis in these hearts was not affected by the presence of amino acids. Choline uptake in the hamster myocytes was also enhanced by neutral amino acid. The enhancement of choline uptake suggests a direct interaction between the amino acid and the transport of choline into the myocardiac cells. The different responses in choline uptake to neutral amino acids indicate that the regulation of choline uptake in the hearts may be different between mammalian species.

Amino Acids↗
PubMed1999

Choline modulates cardiac membrane repolarization by activating an M3 muscarinic receptor and its coupled K+ channel.

Choline is a necessary substrate of the lipid membrane and for acetylcholine synthesis. Accumulating evidence indicates that besides being a structural component, choline is also a functional modulator of the membrane. It has been shown to be a muscarinic acetylcholine receptor (mAChR) agonist and can induce a novel K+ current in cardiac cells. However, the potential role of choline in modulating cardiac functions remained unstudied despite that mAChRs are known to be important in regulating heart functions. With microelectrode techniques, we found that choline produced concentration-dependent (0.1 approximately 10 mm) decreases in sinus rhythm and action potential duration in isolated guinea pig atria. The effects were reversed by 2 nm 4DAMP (an M3-selective antagonist). Whole-cell patch-clamp recordings in dispersed myocytes from guinea pig and canine atria revealed that choline is able to induce a K+ current with delayed rectifying properties. The choline-induced current was suppressed by low concentrations of 4DAMP (2 approximately 10 nm). Antagonists toward other subtypes (M1, M2 or M4) all failed to alter the current. The affinity of choline (Kd) at mAChRs derived from displacement binding of [3H]-NMS in the homogenates from dog atria was 0.9 mm, consistent with the concentration needed for the current induction and for the HR and APD modulation. Our data indicate that choline modulates the cellular electrical properties of the hearts, likely by activating a K+ current via stimulation of M3 receptors.

Animals↗
PubMed1998

Sodium-dependent and -independent choline uptake by type II epithelial cells from rat lung.

The uptake of 3H-labeled choline by a suspension of isolated type II epithelial cells from rat lung has been studied in a Ringer medium. Uptake was linear for 4 min at both 0.1 microM and 5.0 microM medium choline; at 5 microM, only 10% of the label was recovered in a lipid fraction. Further experiments were conducted at the low concentration (0.1 microM), permitting characterization of the properties of high-affinity systems. Three fractions of choline uptake were detected: (i) a sodium-dependent system that was totally inhibited by hemicholinium-3 (HC-3); (ii) a sodium-independent uptake, when Na+ was replaced by Li+, K+ or Mg2+, inhibited by HC-3; (iii) a residual portion persisting in the absence of Na+ and unaffected by HC-3. Choline uptake was sigmoidally related to the medium Na+ concentration. Kinetic properties of the uptake of 0.1 microM 3H-choline in the presence and absence of medium Na+ were examined in two ways. (a) Inhibition by increasing concentrations of unlabeled choline (0.5-100 microM) was consistent with the presence of two Michaelis-Menten-type systems in the presence of Na+; a Na(+)-dependent portion (a mean of 0.52 of the total) had a K(m) for choline of 1.5 microM while K(m) in the absence of Na+ (Li+ substituting) was 18.6 microM. (b) Inhibition by HC-3 (0.3-300 microM) gave Ki values of 1.7 microM and 5.0 microM HC-3 for the Na(+)-dependent and -independent fractions. The apparent K(m) of the Na(+)-dependent uptake is lower than that reported previously for lung-derived cells and is in the range of the K(m) values reported for high-affinity, Na(+)-dependent choline uptake by neuronal cells.

Animals↗
PubMed2004

Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors.

We prospectively assessed and compared the usefulness of 11C-choline positron emission tomography (PET) with that of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) PET for the differentiation between benign and malignant tumors. A total of 126 patients with 130 lesions were studied (25 brain tumors, 51 head and neck tumors, 15 bone tumors, 16 lung tumors, and 23 soft tissue tumors). 11C-choline PET and FDG PET were performed from 5 and 40 min, respectively, after injection of 275-370 MBq tracer. PET data were evaluated using the standardized uptake value (SUV) and were analyzed in accordance with the pathologic data. The 11C-choline uptake in malignancies was 3.9+/-2.3 (n=81), which was significantly higher than that in benign lesions (n=49) (2.6+/-1.7, P<0.005). The FDG uptake in malignancies was 5.9+/-3.8 (n=81) and was also significantly higher than that in benign lesions (2.8+/-2.0, P<0.0001). The 11C-choline uptake in the lesions correlated with FDG uptake (r=0.65, P<0.003). According to an ROC analysis, the areas under the ROC curves (AUCs) for 11C-choline PET were more than 0.8 in bone, head and neck, lung, and soft tissue tumors, while the AUC was 0.79 in brain tumors. The AUCs for FDG PET were similarly more than 0.8 in bone, head and neck, lung, and soft tissue tumors, but had a lower value of 0.585 in brain tumors. In brain, head and neck, bone, and soft tissue tumors, 11C-choline showed higher contrast than FDG. In conclusion, it is feasible to use 11C-choline PET for differentiation between malignant and benign tumours, especially of the brain, head and neck, bone, and soft tissue. However, attention needs to be drawn to the high uptake of 11C-choline in some benign tumors and tumour-like lesions, as this will be of significance in clinical practice.

Adolescent↗
PubMed1998

Basolateral choline transport in isolated rabbit renal proximal tubules.

Choline can undergo both net secretion and net reabsorption by renal proximal tubules, but at physiological plasma levels net reabsorption occurs. During this process, choline enters the cells at the luminal side down an electrochemical gradient via a specific transporter with a high affinity for choline. It appeared likely that choline was then transported out of the cells against an electrochemical gradient at the basolateral membrane by countertransport for another organic cation. This possibility was examined by studying net transepithelial reabsorption and basolateral uptake and efflux of [14C]choline in isolated S2 segments of rabbit renal proximal tubules. Basolateral uptake, which was inhibited by other organic cations such as tetraethylammonium (TEA), appeared to occur by the standard organic cation transport pathway. However, the addition of TEA to the bathing medium not only failed to trans-stimulate net transepithelial reabsorption and basolateral efflux of [14C]choline but it actually inhibited transepithelial reabsorption by @60%. The results do not support the presence of a countertransport step for choline against an electrochemical gradient at the basolateral membrane. Instead, they suggest that choline crosses this membrane by some form of carrier-mediated diffusion even during the reabsorptive process.

Absorption↗
PubMed2006

Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release.

AIMS: Treatments that increase acetylcholine release from brain slices decrease the synthesis of phosphatidylcholine by, and its levels in, the slices. We examined whether adding cytidine or uridine to the slice medium, which increases the utilization of choline to form phospholipids, also decreases acetylcholine levels and release. METHODS: We incubated rat brain slices with or without cytidine or uridine (both 25-400 microM), and with or without choline (20-40 microM), and measured the spontaneous and potassium-evoked release of acetylcholine. RESULTS: Striatal slices stimulated for 2 h released 2650+/-365 pmol of acetylcholine per mg protein when incubated without choline, or 4600+/-450 pmol/mg protein acetylcholine when incubated with choline (20 microM). Adding cytidine or uridine (both 25-400 microM) to the media failed to affect acetylcholine release whether or not choline was also added, even though the pyrimidines (400 microM) did enhance choline;s utilization to form CDP-choline by 89 or 61%, respectively. The pyrimidines also had no effect on acetylcholine release from hippocampal and cortical slices. Cytidine or uridine also failed to affect acetylcholine levels in striatal slices, nor choline transport into striatal synaptosomes. CONCLUSION: These data show that cytidine and uridine can stimulate brain phosphatide synthesis without diminishing acetylcholine synthesis or release.

Acetylcholine↗
PubMed1983

Determination of intracellular choline levels by an enzymatic assay.

A sensitive enzymatic assay for the measurement of intracellular choline is described. The separation of choline from choline-containing phospholipids is accomplished by a minor modification of the Folch technique. The method is based on the specific oxidation of choline by choline oxidase. Phenol and 4-aminoantipyrine in the presence of hydrogen peroxide generated by the oxidation of choline and peroxidase form a red quinone dye which can be detected spectrophotometrically. The assay was useful between 12.5 and 100 nanomoles of choline. The recovery of standard choline in liver homogenates averaged 102 +/- 1.6%. Structurally similar compounds produced minimal interference.

Alcohol Oxidoreductases↗
PubMed1991

Regulation of phosphatidylserine decarboxylase in Saccharomyces cerevisiae by inositol and choline: kinetics of repression and derepression.

The biosynthesis of phosphatidylserine (PS) and its conversion to phosphatidylcholine (PC) are regulated coordinately by inositol and choline in Saccharomyces cerevisiae (G. M. Carman and S. A. Henry, 1989, Annu. Rev. Biochem. 58, 635-669). In this study, PS decarboxylase activity is shown to be partially repressed when inositol is added to the medium of cells in the log phase of growth, and the extent of repression is augmented by the inclusion of choline, but not ethanolamine. The kinetics of repression and derepression of PS decarboxylase, PS synthase, and phospholipid N-methyltransferase (PNMT) activities, as regulatory responses to the availability of exogenous inositol and choline, have been characterized. When inositol was added to the medium of cell cultures growing exponentially, the three biosynthetic enzyme activities reached an intermediate level of repression (50-85% of control) within 60 min. After the addition of the combination of inositol and choline, PS decarboxylase, PS synthase, and PNMT activities decreased to the intermediate levels of repression in 60 min and were subsequently reduced to 15-40% of control values during a later stage of regulation (2-3 h). In a derepression study, the three enzyme activities remained relatively stable for approximately 60 min following the removal of choline and/or inositol from the growth medium, but the specific activities of PS decarboxylase, PS synthase, and PNMT increased to maximally derepressed levels within 2-3 h. The induction of the three biosynthetic activities was blocked by cycloheximide, but not by chloramphenicol. In summary, the level of PS decarboxylase activity in S. cerevisiae is partially and reversibly suppressed by inositol and further diminished by the combination of inositol and choline. The biphasic kinetics of repression by inositol and choline suggest that the effect of choline is dependent on earlier events mediated by inositol and possibly involves a separate regulatory factor(s).

Allosteric Regulation↗