Intestinal transfer of choline in rat and hamster

Sanford, P. A.; Smyth, David

doi:10.1113/jphysiol.1971.sp009497

Cited by 33 publications

(20 citation statements)

References 11 publications

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“…4D) (Werner and Bell, 1921;Ing, 1949). The choline transporter system, which includes CHT and CTLs, plays a significant role in the intestinal absorption of this essential nutrient (Sanford and Smyth, 1971;Herzberg and Lerner, 1973;Kuczler et al, 1977;Kamath et al, 2003). HC3 (1 mM), a specific inhibitor of CHT (IC 50 5 4 nM; Apparsundaram et al, 2000), inhibited metformin AP uptake into Caco-2 cell monolayers by ∼15% (Fig.…”

Section: Discussionmentioning

confidence: 99%

Four Cation-Selective Transporters Contribute to Apical Uptake and Accumulation of Metformin in Caco-2 Cell Monolayers

Han

Proctor

Costales

et al. 2015

J Pharmacol Exp Ther

107

123

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Metformin is the frontline therapy for type II diabetes mellitus. The oral bioavailability of metformin is unexpectedly high, between 40 and 60%, given its hydrophilicity and positive charge at all physiologic pH values. Previous studies in Caco-2 cell monolayers, a cellular model of the human intestinal epithelium, showed that during absorptive transport metformin is taken up into the cells via transporters in the apical (AP) membrane; however, predominant transport to the basolateral (BL) side occurs via the paracellular route because intracellular metformin cannot egress across the BL membrane. Furthermore, these studies have suggested that the AP transporters can contribute to intestinal accumulation and absorption of metformin. Transporter-specific inhibitors as well as a novel approach involving a cocktail of transporter inhibitors with overlapping selectivity were used to identify the AP transporters that mediate metformin uptake in Caco-2 cell monolayers; furthermore, the relative contributions of these transporters in metformin AP uptake were also determined. The organic cation transporter 1, plasma membrane monoamine transporter (PMAT), serotonin reuptake transporter, and choline high-affinity transporter contributed to approximately 25%, 20%, 20%, and 15%, respectively, of the AP uptake of metformin. PMATknockdown Caco-2 cells were constructed to confirm the contribution of PMAT in metformin AP uptake because a PMAT-selective inhibitor is not available. The identification of four intestinal transporters that contribute to AP uptake and potentially intestinal absorption of metformin is a significant novel finding that can influence our understanding of metformin pharmacology and intestinal drug-drug interactions involving this highly prescribed drug.

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Section: Discussionmentioning

confidence: 99%

Four Cation-Selective Transporters Contribute to Apical Uptake and Accumulation of Metformin in Caco-2 Cell Monolayers

Han

Proctor

Costales

et al. 2015

J Pharmacol Exp Ther

107

123

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“…Choline transport by the intestine has been described previously in the adult hamster, rat, guinea pig and chick (19,21,22). Within the small intestine of these species, choline transport occurred by both a saturable and a nonsaturable process.…”

Section: -------------------~8mentioning

confidence: 99%

An in Vitro Study of Choline Uptake by Intestine from Neonatal and Adult Rats

Sheard

Zeisel

1986

Pediatr Res

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MATERIALS AND METHODSthe developing small intestine are frequently different from those characterized in the intestine of mature animals (9-13).In the present studies, we examined the kinetics of choline uptake in the developing small intestine and compared these transport characteristics with those found in the intestine of mature animals.Animals. Adult, male Sprague-Dawley rats (Charles River Breeding Laboratory, Wilmington, MA), each weighing 100-125 g, were housed in stainless steel cages. Rat Chow (Ralston Purina, St. Louis, MO; 0.16% unesterified choline by our assay) and water were given ad libitum for 1 wk prior to use in our studies. Temperature in the housing facility was 24°C. The light cycle was 12 h long, 0600 to 1800 h.Neonatal animals used in these studies were kept with lactating dams up to the time of the experiment. Litter size was limited to 10 pups per dam. Mothers were fed rat Chow (Ralston Purina; 0.16% unesterified choline by our assay) and water ad libitum. Rat milk contained 100-300 ILM unesterified choline by our assay. Only male rat pups, 10-11 days old, were used in the experiments described. Measurement o/uptake by gut slices. Adult rats were anesthetized with ether, a midline abdominal incision was made, and the small intestine was visualized. Segments taken from the area immediately distal to the end of the stomach were designated as duodenum. Jejunal segments were taken from the area whose blood supply was derived from the jejunal artery. Ileal segments were taken from the area 10 cm proximal to the cecum. Colonic segments were taken from the area immediately distal to the cecum. In the 10-day-old rat, segments ofjejunum were collected from the small intestine from the area whose blood supply was derived from the jejunal artery.Gut sections were removed and placed in ice-cold KRB containing 10 mM glucose. They were cut longitudinally, rinsed with KRB, and trimmed to a length of 2 cm. These tissue slices were supported on filter paper (Whatman no. 3) and placed in a prewarmed (3r C), modified~Ussing chamber containing KRB in the bottom portion of the chamber (11,18). The top of the chamber was positioned over the gut slice and clamped down. KRB containing choline, 14C-choline, 3H-inulin, and nonradiolabeled inulin (or 3H-D-glucose and D-glucose) was added to this upper chamber. A gas containing 95% oxygen and 5% carbon dioxide was bubbled through the medium throughout the 15-min incubatinn period. 768 Abbreviations KRB, Krebs' Ringer buffer containing 10 mM glucose TLC, thin-layer chromatography

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“…Welsch (1976aWelsch ( , 1978 observed a 65 % inhibition of choline accumulation by placental fragments after 30 min of incubation with these inhibitors. In the intestine (Kuczler et al 1977;Sanford & Smyth, 1971) and synaptosomes (Marchbanks, 1968) there was also a small effect of these metabolic inhibitors on choline accumulation.…”

Section: Effects Of Inhibitors Of Aerobic Metabolismmentioning

confidence: 99%

“…In the intestine, the transport of choline has been shown to be a sodium-independent process (see review by Rose, 1980) in the chick (Herzberg & Lerner, 1973), guinea-pig (Kuczler et al 1977) and hamster (Sanford & Smyth, 1971), and in rat brush-border membrane vesicles (Kessler, Acuto, Storelli, Murer, Muller & Semenza, 1978). In the red cell choline fluxes do not appear to be sodium-dependent provided sodium is replaced with magnesium or calcium (Martin, 1972).…”

Section: Placental Choline Transportmentioning

confidence: 99%

Characterization of choline transport at maternal and fetal interfaces of the perfused guinea‐pig placenta.

Sweiry¹,

Yudilevich²

1985

The Journal of Physiology

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SUMMARY1. Unidirectional influx and efflux of choline into the syncytiotrophoblast were investigated from both maternal and fetal circulations of the perfused guinea-pig placenta by using a single-circulation paired-tracer (extracellular reference and test substrate) dilution technique.2. Cellular uptake of [3H]choline at 0 05 mm was (mean percentage ± S.E. of mean, n = 14 placentae) 51 + 2 and 49 + 2, on maternal and fetal sides, respectively. Kinetics ofunidirectional influx (0 05-4 0 mM-choline) indicated the existence of saturable and noi-saturable components on both sides: on maternal and fetal interfaces the Km (mM) values were respectively, 0-12 and 0413, the Vmax (flmol min-g-1) values, 0-08 and 0-07 and the apparent linear transfer constants (min' ge1) 0-11 and 0-12.3. Efflux of [3H]choline from the placenta back into the ipsilateral circulation (backflux) was generally fast (20-60% in 5-6 min) and asymmetric with the fetal: maternal ratio usually above unity. Transplacental specific choline transfer in the dually perfused placenta, when observed, was small (< 10 % of the injected dose) following tracer injections in either direction based on the 56 min collection of the contralateral circulation (at 0-05 mM-choline). Placental retention of [3H]choline at the end of the 5-6 min period was about 25 % of the injected dose when the tracers were injected from either circulation.4. Analogues of choline such as hemicholinium-3, thiamine, ethanolamine and N,N-dimethylethanolamine inhibited choline unidirectional influx, whereas betaine and acetate had no effect.5. The absence of the normal sodium gradient (perfusate sodium was replaced by Tris or by lithium) did not inhibit choline transport. The metabolic inhibitors dinitrophenol (1-0 mM) and potassium cyanide (1D0 mM) were essentially ineffective (up to 40 min perfusion). The sulphydryl reagent N-ethylmaleimide did not appear to inhibit the influx, in comparison with its effect on [3H]choline backflux which was greatly accelerated, resulting in a dramatic reduction in placental net uptake of the label.6. Our findings show that choline transport into the placenta is a rapid carriermediated process occurring at both maternal and fetal sides of the trophoblast, at physiological blood concentrations. This cellular uptake is possibly related to the synthesis of acetycholine, which is known to occur in human placental tissue. Specific

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Intestinal transfer of choline in rat and hamster

Cited by 33 publications

References 11 publications

Four Cation-Selective Transporters Contribute to Apical Uptake and Accumulation of Metformin in Caco-2 Cell Monolayers

Four Cation-Selective Transporters Contribute to Apical Uptake and Accumulation of Metformin in Caco-2 Cell Monolayers

An in Vitro Study of Choline Uptake by Intestine from Neonatal and Adult Rats

Characterization of choline transport at maternal and fetal interfaces of the perfused guinea‐pig placenta.

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