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PubMed2004

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: CDP-choline is used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to which the treatments was given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. OBJECTIVES: The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 20 January 2004 using the terms CDP-choline, CDP, citicolone, cytidine diphosphate choline or diphosphocholine. This register contains records from all major health care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders are considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 4 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies were heterogeneous in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of CDP-choline on attention. There are significant beneficial effects of CDP-choline on memory function and behaviour. The drug is well tolerated. REVIEWERS' CONCLUSIONS: There is some evidence that CDP Choline has a positive effect on memory and behaviour in at least the short/medium term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially vascular dementia.

Aged↗
PubMed2002

Evaluation of the inhibition of choline uptake in synaptosomes by capillary electrophoresis with electrochemical detection.

A direct method for evaluating choline uptake by the high-affinity choline transport system in synaptosomes was developed using capillary electrophoresis (CE) with electrochemical (EC) detection. On-column EC detection of choline and the internal standard, butyrylcholine, was accomplished with a 25 microm platinum electrode modified with the enzymes, choline oxidase and acetylcholinesterase. Choline uptake was evaluated as a function of choline concentration and a KM value of 1.7 microM was determined. The method was also used to evaluate a new class of redox affinity inhibitors of choline transport. In particular, the effectiveness of 3-[(trimethylammonio)methyl]catechol (TMC) as an inhibitor of choline uptake was examined independently and relative to the inhibition of the well-known inhibitor of choline transport, hemicholinium-3. The IC50 and KI for TMC were determined to be 30 microM and 14 microM, respectively. The combination of the selectivity and sensitivity afforded by CEEC provides a relatively straightforward approach for monitoring choline transport in synaptosomes.

Acetylcholinesterase↗
PubMed1978

Deanol acetamidobenzoate inhibits the blood-brain barrier transport of choline.

Competition by deanol (dimethylaminoethanol) with choline for uptake from the bloodstream into the brain was demonstrated by simultaneous intracarotid administration of carbon 14-labeled choline with deanol (plus tritiated water and indium 113m, to calculate a brain uptake index) and by measuring the brain uptake of 14C-labeled choline mixed with sera from rats pretreated with deanol (300 or 500 mg/kg 8 or 30 minutes earlier). The inhibition constant for inhibition of choline uptake by deanol (159 micrograms) was actually lower than the Michaelis constant for choline itself (442 micrograms); hence, the affinity of the carrier mechanism for deanol is at least as great as it is for choline. Deanol administration also elevated blood choline levels; thus, the effect of the drug on brain choline (and acetylcholine) levels is the result of the increase it produces in blood choline and the suppression it causes in choline uptake. These findings may explain discrepant results from laboratories seeking increases in brain acetylcholine or clinical improvement in patients with tardive dyskinesia after deanol treatment.

Acetylcholine↗
PubMed1998

The choline kinase inhibitor hemicholinium-3 can inhibit mitogen-induced DNA synthesis independent of its effect on phosphocholine formation.

In NIH 3T3 cells, phosphocholine (PCho) stimulates mitogenesis in synergism with insulin, ATP, and sphingosine-1-phosphate (S1P) via an extracellular target. Intracellular PCho also has been suggested to mediate the mitogenic effects of fibroblast growth factor (FGF) and several other growth factors based, in part, on the observed inhibition of growth factor-induced mitogenesis by the choline kinase inhibitor hemicholinium-3 (HC-3). Here we examined the specificity of HC-3 effects on mitogenesis in serum-starved NIH 3T3 and Swiss 3T3 cells. In both cell lines, FGF greatly enhanced DNA synthesis in a medium containing 28 microM choline, and it also stimulated the formation of -14C-PCho from both 50 microM and 5 mM [14C]choline. HC-3 (2 mM) inhibited basal or FGF-induced formation of [14C]PCho and [14C]phosphatidylcholine as well as the uptake of -14C-choline only at the 50 microM, but not the 5 mM, concentration of [14C]choline. In addition, HC-3 (1 mM) from three different sources (95-99.9% purity) inhibited FGF-stimulated DNA synthesis by 53-58% which was not reversed by 5 mM choline. The choline analogue dimethylethanolamine (1 mM) also inhibited FGF-stimulated formation of [14C]PCho from 50 microM -14C-choline, but it had no effect on FGF-induced DNA synthesis. Of the other growth regulators examined, synergistic stimulation of DNA synthesis by extracellular PCho and S1P or PCho and ATP via choline kinase-independent mechanisms was inhibited by 2 mM HC-3. However, HC-3 failed to inhibit the synergistic mitogenic effects of PCho and insulin or S1P and insulin. The results suggest that FGF-induced mitogenesis does not require PCho formation and that HC-3 can inhibit DNA synthesis independent of its inhibitory effects on choline metabolism.

3T3 Cells↗
PubMed1998

Conductive choline transport by alveolar epithelial plasma membrane vesicles.

Choline is an important substrate in alveolar epithelia for both surfactant production and cellular maintenance. The underlying mechanisms of uptake and sites of membrane transport remain uncertain. To test the hypothesis that choline transport occurs at the basolateral side of alveolar epithelia by both Na+-independent and -dependent mechanisms, plasma membrane vesicles were prepared from the apical and basolateral membranes of mature porcine type II pneumocytes. Choline+ transport was assayed by uptake of [3H]choline+ by enriched apical or basolateral vesicles. In the presence of imposed, inside-negative charge gradients, basolateral vesicles exhibited early overshoot of [3H]choline+ uptake unaffected by the presence or absence of external Na+ (541 +/- 53 vs 564 +/- 79 pmol/mg protein (NS)). High sensitivity to hemicholinium-3 was observed in the presence or absence of Na+. In the absence of inside-negative charge gradients, uptake was reduced 12-fold in the presence or absence of Na+, and external choline+ induced internal alkalization of acidified basolateral vesicles. Accumulative [3H]choline+ uptakes by apical vesicles in the presence or absence of inside-negative charge gradients and Na+ were insignificant. We conclude that predominant choline+ uptake by type II pneumocytes occurs at the basolateral membrane by Na+-independent, electrogenic choline+ conductance. The presence of electroneutral choline+/H+ exchange is suggested.

Animals↗
PubMed1986

Characterization of choline efflux from the perfused heart at rest and after muscarine receptor activation.

The resting efflux of choline from perfused chicken hearts varied from 0.4 to 2.6 nmol/g min, but was constant for at least 80 min in the individual experiments. The rate of choline efflux was found to be equal to the rate of choline formation in the heart, which, from the following reasons, was essentially due to hydrolysis of choline phospholipids. Cardiac content of choline phospholipids (7,200 nmol/g) was much higher than that of acetylcholine (5.5 nmol/g). Resting release of acetylcholine was 0.016 nmol/g min and, after inhibition of cholinesterase, only about 0.1 nmol/g min. Resting efflux of choline was reduced by mepacrine, a phospholipase A2 inhibitor, by perfusion with a Ca2+-free Tyrode's solution containing EGTA and by the combination mepacrine plus Ca2+-free/EGTA solution. In all experiments the reduced choline efflux levelled off within 10 min at about 50%. Omission or elevation of Mg2+ from 1.05 to 10.5 mmol/l had no effect. Resting efflux was increased to 150% by oleic acid (as sodium salt; 2 X 10(-5) mol/l) which is known to activate phospholipase D. Likewise muscarinic agonists (carbachol and acetylcholine) caused facilitation of the efflux of endogenous choline that was blocked by 3 X 10(-7) mol/l atropine. This effect was not reduced, but even slightly enhanced, by mepacrine and by infusion of EGTA in a modified Tyrode's solution (Ca2+-free, 10.5 mmol/l Mg2+). It is concluded that the resting efflux of choline from the heart is essentially due to hydrolysis of choline phospholipids, that half of the efflux is insensitive to mepacrine and is Ca2+-independent (excluding an involvement of phospholipase A2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Effect of ethanol ingestion on choline phosphotransferase and phosphatidyl ethanolamine methyltransferase activities in liver microsomes.

The effect of ethanol ingestion on choline phosphotransferase and phosphatidyl ethanolamine methyltransferase activities, the two enzymes involved in phosphatidyl choline biosynthesis in liver microsomes, has been investigated. Female rats were fed a 5% ethanol-liquid diet containing amino acids, minerals, vitamins, with and without choline, for 2, 6 and 10 weeks. Control animals were pair-fed the same isocaloric diet with 5% sucrose with and without choline. Ethanol administration with or without dietary choline stimulated significantly (P less than 0.001) the specific activities of phosphatidyl ethanolamine methyltransferase in liver microsomes in the animals fed 5% ethanol for 2, 6, and 10 weeks, when compared to those control animals pair-fed the isocaloric diet with or without choline. Ethanol administration with or without dietary choline for 2 weeks stimulated significantly (P less than 0.02) the specific activities of choline phosphotransferase. The specific activities of phosphatidyl ethanolamine methyltransferase continued to increase in the liver microsomes from the animals in which dietary choline was omitted for 2, 6, and 10 weeks in the sucrose controls and alcohol-fed animals. Ethanol administration stimulates significantly (P less than 0.001) the phosphatidyl ethanolamine methyltransferase specific activities in liver microsomes of animals fed the liquid diet with dietary omission of choline and methionine for 2 weeks.

Alcohol Drinking↗
PubMed1976

Phospholipid synthesis in mammary tissue. Choline and ethanolamine kinases: kinetic evidence for two discrete active sites.

Choline and ethanolamine kinases are located in the high speed supernatant of lactating bovine mammary gland. Maximum activities of choline and ethanolamine kinases were observed at pH 9.2 and 8.0, respectively, with the rate of ethanolamine phosphorylation being 1/15 that of choline phosphorylation. Activation energies of 29 joules (Q10--1.5) and 31 joules (Q10 = 1.5) were calculated between 3.4 and 31.3 C for choline kinase and ethanolamine kinase, respectively. Above 31.3 C, the Arrhenius plot deviated from linearity for both enzymes, suggesting that denaturation was occurring. An apparent Km of 0.25 mM for choline was obtained for choline kinase activity. The apparent Km of ethanolamine kinase for ethanolamine was unusually high (17 mM), the activity was not linear with increasing protein concentration. Activity was tripled and the Km decreased to 2.5 mM when the enzyme preparation was washed with butanol: benzene mixture, suggesting the presence of an endogenous competitive inhibitor(s), with respect to ethanolamine. Choline kinase was not affected by the solvent wash. Substrate competition studies revealed that choline kinase was slightly inhibited competitively by ethanolamine (apparent Ki = 19-21 mM), whereas choline was a potent competitive inhibitor of ethanolamine kinase (apparent Ki = 0.33-0.50 mM). The results indicated that these two kinase activities were mediated by two distinct active sites, possibly on a single protein. The significance of choline in the regulation of phosphatidylethanolamine synthesis is discussed.

Animals↗
PubMed2005

Donepezil, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN) inhibit choline transport by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB).

In the present study, we have characterized the choline transport system and examined the influence of various amine drugs on the choline transporter using a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) in vitro. The cell-to-medium (C/M) ratio of [3H]choline in TR-BBB cells increased time-dependently. The initial uptake rate of [3H]choline was concentration-dependent with a Michaelis-Menten value, Km, of 26.2 +/- 2.7 microM. The [3H]choline uptake into TR-BBB was Na+-independent, but was membrane potential-dependent. The [3H]choline uptake was susceptible to inhibition by hemicholinium-3, and tetraethylammonium (TEA), which are organic cation transporter substrates. Also, the uptake of [3H]choline was competitively inhibited with Ki values of 274 microM, 251 microM and 180 microM in the presence of donepezil hydrochloride, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN), respectively. These characteristics of choline transport are consistent with those of the organic cation transporter (OCT). OCT2 mRNA was expressed in TR-BBB cells, while the expression of OCT3 or choline transporter (CHT) was not detected. Accordingly, these results suggest that OCT2 is a candidate for choline transport at the BBB and may influence the BBB permeability of amine drugs.

Animals↗
PubMed2000

Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography.

[methyl-11C]choline (11C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of 11C-choline uptake, blood metabolism of 11C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of 11C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered 11C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized 11C-choline in rat plasma decreased from 42% +/- 20% (mean +/- SD) at 5 min to 21% +/- 10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized 11C-choline represents 62% +/- 19% of the total radioactivity in arterial plasma at 5 min after injection and 27% +/- 12% at 15 min. In human venous plasma the corresponding values were 85% +/- 12% and 48% +/- 12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as 11C-betaine. In human arterial plasma this maximally represented 82% +/- 9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the 11C-choline and 11C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating 11C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection.

Animals↗
PubMed2003

Kinetics of [(11)C]choline uptake in prostate cancer: a PET study.

Carbon-11 choline has recently been introduced as a potential tracer for tumour imaging with positron emission tomography (PET). We evaluated the kinetics of the uptake of [(11)C]choline in prostate cancer and benign prostatic hyperplasia. We also evaluated the association between the uptake of [(11)C]choline and the histological grade of malignancy, Gleason score, volume of the prostate and prostate-specific antigen (PSA). Fourteen patients with histologically confirmed prostate cancer and five patients with benign prostatic hyperplasia were studied with [(11)C]choline PET. A mean dose of 430+/-31 MBq of [(11)C]choline was injected intravenously and a dynamic emission acquisition of prostate was performed for 30 min. The uptake of [(11)C]choline was measured as a standardised uptake value (SUV) and as a kinetic influx constant ( K(i)) obtained from graphical analysis. Both cancerous and hyperplastic prostate were well visualised with [(11)C]choline against low or moderate tracer accumulation in the bladder and rectal wall. The measured radioactivity in urine was invariably low. In the graphical analysis, linear plots were achieved. The mean K(i) of the untreated tumour was 0.205+/-0.089 min(-1) (range 0.128-0.351; n=7) and the mean SUV was 5.6+/-3.2 (range 1.9-15.5; n=15). K(i) values and SUVs correlated closely ( r=0.964, P=0.0005), whereas no correlation could be demonstrated between the tumour uptake of [(11)C]choline and the histological grade, Gleason score, volume of the prostate or PSA. The mean SUV and the mean K(i) of benign hyperplastic prostate were 3.5+/-1.0 (range 2.0-4.5; n=4) and 0.119+/-0.076 min(-1) (range 0.065-0.173; n=2). In conclusion, a high uptake of [(11)C]choline characterises not only carcinomatous but also hyperplastic prostatic tissue. Dynamic imaging of the uptake of [(11)C]choline in the prostate shows a good applicability of the graphical analysis model with an irreversible compartment. A close correlation between the K(i) values and semiquantitative SUVs of tumours supports the use of the simpler SUV in the clinical setting.

Aged↗
PubMed2001

Brain tumour imaging with carbon-11 choline: comparison with FDG PET and gadolinium-enhanced MR imaging.

The purpose of this study was to assess the clinical potential of methyl-11C-choline (11C-choline) in the diagnosis of brain tumours. To this end, the results of 11C-choline positron emission tomography (PET) in 22 patients suspected of having brain tumours were compared with the findings of contrast-enhanced magnetic resonance (MR) imaging and fluorine-18 fluorodeoxyglucose PET. A histopathological diagnosis was made for each patient during open surgery. The standardised uptake values of brain tumours and the tumour-to-white matter count (T/W) ratios were determined. The degree of 11C-choline accumulation noted in PET images was compared with the gadolinium-enhanced areas of MR images. The mean T/W ratio of 11C-choline in high-grade gliomas was found to be higher than that in low-grade gliomas. This difference was statistically significant (mean+/-SD: 8.7+/-6.2, n=9 versus 1.5+/-0.7, n=5, P<0.03) when data pertaining to the prominent uptake of 11C-choline in a patient with a pilocytic astrocytoma were excluded. 11C-choline PET failed to detect non-neoplastic lesions in two patients. Areas of 11C-choline accumulation in PET scans were larger than areas enhanced on MR images in five cases involving high-grade gliomas. 11C-choline PET differentiated between low-grade gliomas and high-grade gliomas, but did not differentiate between low-grade gliomas and non-neoplastic lesions. The combination of 11C-choline PET and MR imaging may provide investigators with an accurate means by which to identify high-grade gliomas.

Adolescent↗
PubMed1979

Cation-induced asymmetry of choline flux across presynaptic plasma membranes.

Highly cholinergic synaptosomes from the optic lobes of Sepia officinalis retain their ability to concentrate K+ and extrude Na+ sensitive but is not obligatorily coupled to choline metabolism, or an energy supply as shown by the action of metabolic and ion pump inhibitors. The influx and efflux and/or steady-state distributions of choline in the presence of Na+, Li+, Rb+, Cs+ and mannitol were studied. The influx studies at different cis-choline concentrations revealed two systems for choline influx with different monovalent cation sensitivity and suggested a 1 : 1 interaction of choline with both mechanisms. Choline efflux was stimulated by trans-choline. Calculations of the internal/external concentration ratio expected if choline transport were coupled to the Na+ gradient gave a maximal value of about 10(2). A secondary active transport of choline, where Na+ is the driver solute provides an explanation for the cation sensitivity of the mechanism as well as for the method of coupling of choline transport to the varying demands of the nervous system for acetylcholine.

Animals↗
PubMed1992

Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane.

The characteristics of the intestinal transport system for choline were investigated using isolated brush-border membrane vesicles from rat small intestine. In spite of the diminutive lipid solubility, the uptake of choline by membrane vesicles reflected smooth permeation into intravesicular space rather than the binding to the membrane surface. Physiological conditions, present in the intact intestine, such as an inward-directed Na+ or H+ gradient and inside negative membrane potentials, didn't directly involve in choline transport across the brush-border membrane. Moreover, an outward-directed H+ gradient had no significant effect on the time course of choline transport. However, in the absence of a driving-force, the initial uptake of choline exhibited a saturable manner. A kinetic analysis of the initial uptake rate gave an apparent Km of 159 microM. Furthermore, unlabeled choline caused both cis-inhibition and trans-stimulation for labeled choline transport, suggesting the existence of a carrier-mediated transport system for choline, classified as so-called 'facilitated diffusion'. Since tetramethylammonium, acetylcholine, and N1-methylnicotinamide caused both cis-inhibition and trans-stimulation, they appear to be accepted as the substrate of choline carrier. On the other hand, quaternary ammonium compounds (QACs) such as those which possessed hydrophobic parts in their molecules exhibited only cis-inhibition. They also inhibited Na(+)-dependent D-glucose transport, indicating that they influenced various carrier-mediated transport systems non-specifically due to interaction with the membrane. These findings strongly suggest that the choline transport system on the brush-border membrane of rat intestine recognizes only small molecular QACs as its substrate.

Animals↗
PubMed1993

The cation receptor subsite of the choline transporter in preimplantation mouse conceptuses resembles a cation receptor subsite of several amino acid transporters.

Mediated choline transport in preimplantation mouse conceptuses was inhibited competitively by Na+ and other cationic osmolites. Uptake of choline by conceptuses was also inhibited relatively strongly by ethanolamine, hemicholinium-3, harmaline, harmalol and harmine. The Ki values for inhibition of choline transport by most of the latter inhibitors were of the same order of magnitude as the Km value for choline transport (approximately 100 microM). To our knowledge, we are the first to show that mediated 'Na(+)-independent' choline transport is, nevertheless, inhibited strongly by the Na(+)-site inhibitor, harmaline. Inhibitions by harmaline, Na+ and other cations have been used to draw a parallel between the substrate receptor sites of amino acid transport systems y+ and bo.+. We suggest that the latter parallel should be extended to include the Na(+)-independent mammalian choline transporter. In addition, the choline transport activity in conceptuses increased by more than 100-fold between the 2-cell and blastocyst stages of development. Mouse blastocysts probably utilize choline for the synthesis of membrane phospholipids during cellular differentiation and when they begin to grow about ten hours prior to implantation. Since we show here that mouse conceptuses develop the capacity to transport choline prior to the onset of growth, some of the choline utilized for growth could come from an exogenous source.

Amino Acid Transport Systems↗
PubMed1988

Structure-activity studies on inhibition of choline uptake by a mouse brain synaptosomal preparation: basic data.

Over 80 substances were studied for their inhibition of high-affinity uptake of [3H]choline into a mouse brain synaptosomal fraction. Kinetic experiments tested a number of them for competitive behavior. A minimal provisional model for the choline uptake process is envisioned that is consistent with current data and with relevant observations in the literature. There are two hydrophilic anionic sites on the choline transporter that are separated from each other by a cationic hydrophobic domain. Association of choline in a Na+-dependent manner with one or both of the sites is necessary for the transport of choline to take place. The choline binding anionic sites are sufficiently large and/or flexible to allow attachment of cationic moieties larger than choline. The cationic hydrophobic domain of the transporter is flexible, probably tending to planarity. The length of the hydrophobic region between the anionic sites is approximately that of 10 extended methylene groups, and the minimal width is approximated by the distance across the condensed ring system of chlorpromazine. The probability of attachment of the highly hydrophilic choline to its binding sites is increased both by hydrogen-bonding to a proton-acceptor within the anionic sites and by repulsion from the cationic hydrophobic region. A number of substances that potently and competitively inhibit high affinity choline uptake possess quaternary ammonium groups and neutral or negatively charged lipophilic groups. In general, substances in which two quaternary ammonium groups are separated by an appropriately configured hydrophobic group and which can combine with both anionic sites and the hydrophobic region between them are more potent inhibitors than monoquaternary substance with the same or similar groups. However, substances with a single high-affinity quaternary group and an appropriately structured hydrophobic group, e.g. the trimethoxy-3-butynyl quaternary ammonium compounds, possess inhibitory efficacies similar to those shown by the most potent bisquaternaries. The above suggests that further delineation of the characteristics of the structures of the above sites of the transporter could lead to devisal of more potent reversible inhibitors of choline uptake than now are available.

Animals↗
PubMed1990

Effect of amiodarone and desethylamiodarone on choline uptake and phosphatidylcholine biosynthesis in cultured chick cardiac myocytes.

The objective of the study was to examine the hypothesis that amiodarone and its major metabolite desethylamiodarone alter choline uptake and metabolism in cardiac myocytes. Myocardial cells were obtained from 7-day-old chick embryos and were maintained in culture. Choline uptake, examined using [methyl 3H] choline, involves saturable and non-saturable processes. Amiodarone and desethylamiodarone at 10(-6) to 10(-4) M produced a significant (P less than 0.05) dose dependent reduction in choline uptake and inhibited the specific or carrier-mediated uptake process. The highest concentrations of each of these agents profoundly reduced choline uptake. Pulse chase experiments using [methyl 3H] choline showed that after a 2-h incubation with choline, about 85% of the label was recovered in phosphocholine, with the majority of the rest in phospholipid that was mainly phosphatidylcholine. Amiodarone and desethylamiodarone did not produce relevant alterations in choline metabolism namely phosphatidylcholine biosynthesis as neither drug altered the rate of disappearance of the label from phosphocholine or the appearance in phospholipid. Amiodarone but not desethylamiodarone produced a small but significant (P less than 0.05) increase in the amount of label that accumulated in CDP choline. These data demonstrate that amiodarone and desethylamiodarone decrease choline uptake into cardiac cells that may potentially be involved in either the mechanism of action or toxicity of amiodarone.

Amiodarone↗
PubMed1988

Fewer metabolites of dietary choline reach the blood of rats after treatment with lithium.

Choline is an important precursor for the biosynthesis of acetylcholine, phosphatidylcholine and sphingomyelin. It is also a major source of labile methyl groups. Lithium is an important component of the treatment of bipolar affective illness, and it inhibits choline transport across membranes. We studied the effect of lithium treatment upon the appearance in blood, liver and intestine of metabolites formed from dietary choline. Rats were treated for 9 days with 2 mEq/kg lithium carbonate or water. Animals were fasted overnight, and on the 10th day were fed with a solution containing radiolabeled choline chloride. The lithium-treated groups also received 2.0 mEq/kg lithium as part of this solution. After an oral dose of 1 ml of a 1 mM choline solution, the lithium-treated animals had significantly lower levels of choline-derived radiolabel in blood than did controls at 30, 60, 120, and 180 minutes (47% (+/- 5%; SEM), 51% (+/- 7%), 59% (+/- 4%) and 74% (+/- 9%), respectively). We observed similar decreases of the accumulation in blood, at 180 minutes after the dose, of choline-derived radiolabel when choline was administered at lower or higher concentrations. After an oral treatment containing 0.1, 1 or 10 mM choline, lithium treated animals accumulated 69% (+/- 6%; SEM), 66% (+/- 11%) and 72% (+/- 7%) as much radiolabel in serum as did controls. Most of the radiolabel found in blood at 180 minutes was in metabolites of choline which are formed within liver (betaine and phosphatidylcholine). The diminished accumulation of radiolabel in serum after lithium treatment was not due to increased accumulation of label by erythrocytes, liver or gut wall. We suggest that lithium influences the release by liver of betaine and phosphatidylcholine.

Animals↗