Absorption of folate by Caco-2 cells is not affected by high glucose concentration

Martel, Fátima; Gonçalves, Pedro; Azevedo, Isabel

doi:10.1016/j.ejphar.2006.09.004

Cited by 12 publications

(6 citation statements)

References 25 publications

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“…Immunofluorescence studies revealed that BCRP is mainly located in the intracellular compartment of Caco‐2 cells, both the HF and the LF‐adapted cell lines. This result is in agreement with recent findings demonstrating that BCRP is not involved in folate efflux in Caco‐2 cells 41. In MCF‐7/MR cells, where folate deprivation induced loss of BCRP expression,25 BCRP is mainly located in the plasma membrane,25, 38 and is actively pumping its substrates out of the cell 25, 42.…”

Section: Discussionsupporting

confidence: 93%

Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco‐2 cells

Lemos

Kathmann

Giovannetti

et al. 2008

Intl Journal of Cancer

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Folates can induce the expression and activity of the breast-cancer-resistance-protein (BCRP) and the multidrug-resistance-protein-1 (MRP1). Our aim was to study the time-dependent effect of folate deprivation/supplementation on (i) BCRP and MRP expression and (ii) on drug resistance mediated by these transporters. Therefore Caco-2 colon cancer cells usually grown in standard RPMI-medium containing supraphysiological folic acid (FA) concentrations (2.3 lM; high-folate, HF) were gradually adapted to more physiological folate concentrations (1 nM leucovorin (LV) or 1 nM FA; low-folate, LF), resulting in the sublines Caco-2-LF/LV and Caco-2-LF/FA. Caco-2-LF/LV and LF/FA cells exhibited a maximal increase of 5.2-and 9.6-fold for BCRP-mRNA and 3.9-and 5.7-fold for BCRP protein expression, respectively, but no major changes on MRP expression. Overexpression of BCRP in the LF-cells resulted in 3.6-to 6.3-fold resistance to mitoxantrone (MR), which was completely reverted by the BCRP inhibitor Ko143. On the other hand, LF-adapted cells were markedly more sensitive to methotrexate than the HF-counterpart, both after 4-hr (9,870-and 23,923-fold for Caco-2-LF/LV and LF/FA, respectively) and 72-hr (11-and 22-fold for Caco-2-LF/LV and LF/FA, respectively) exposure. Immunofluorescent staining observed with a confocal-laser-scan-microscope revealed that in Caco-2 cells (both HF and LF), BCRP is mainly located in the cytoplasm. In conclusion, folate deprivation induces BCRP expression associated with MR resistance in Caco-2 cells. The intracellular localization of BCRP in these cells suggests that this transporter is not primarily extruding its substrates out of the cell, but rather to an intracellular compartment where folates can be kept as storage. ' 2008 Wiley-Liss, Inc.Key words: BCRP (ABCG2); Caco-2 cells; folate; mitoxantrone; multidrug resistance Folate supplementation is increasingly an essential part of current cancer chemotherapeutic regimens, because it reduces toxicity and enhances the efficacy of several chemotherapy-based treatments. Supplementation of the folates leucovorin (LV) or folic acid (FA) is a common practice to reduce methotrexate (MTX) toxicity in leukemia or rheumatoid arthritis 1,2 while LV increases the efficacy of 5-fluorouracil in some solid tumors, especially colon cancer.3,4 A recent clinical study showed that FA supplementation reduced toxicity of the combination of the antifolate pemetrexed with cisplatin.5 Interestingly, FA also increased the efficacy of this combination, and of cisplatin as a single drug. Homocysteine appeared to be good predictive factor for severe toxicity caused by pemetrexed.6 Therefore, further development of pemetrexed-based therapies has been changed by the addition of FA and vitamin B 12 to all treatment protocols. 5,7 In addition, individual patients may take vitamin supplements themselves during treatments.Some ATP-binding cassette (ABC) transporters have the ability to transport folates and antifolates such as MTX.8 Multidrug resistance proteins 1 through 4 (MRP...

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Section: Discussionsupporting

confidence: 93%

Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco‐2 cells

Lemos

Kathmann

Giovannetti

et al. 2008

Intl Journal of Cancer

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“…Moreover, high-glucose levels cause an inhibition of the activity and expression of OCT3 24 and RFC1, 23 although they did not affect the intestinal absorption of folic acid. 30 The importance of the results presented in this work relates to the physiological role of SERT in the human organism. Three of the important locations of SERT are at the CNS, gastrointestine and placenta.…”

Section: Discussionmentioning

confidence: 96%

The effect of high glucose on SERT, the human plasmalemmal serotonin transporter

Gonçalves

Araújo

Martel

2008

Nutritional Neuroscience

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The aim of this work was to investigate the effect of short- and long-term high-glucose exposure on the plasmalemmal serotonin transporter (SERT)-mediated uptake of [(3)H]-serotonin (5-HT) by Caco-2 cells. Short-term exposure of Caco-2 cells to high apical glucose levels (30 mM for 2 h or 40 mM for 1 h) decreased the uptake of [(3)H]-5-HT by 20-30%. On the other hand, long-term (21-24 weeks) exposure of the cells to high (25 mM) glucose caused a 30% increase in the uptake of [(3)H]5-HT. Under these conditions, the affinity of the transporter for 5-HT and noradrenaline was not significantly changed, and the inhibitory potencies of fluoxetine and desipramine were also unchanged. In conclusion, high-glucose levels modulate SERT activity. A short-term exposure of the cells to a high concentration of glucose decreases the activity of the transporter, whereas a longer exposure of the cells to a high concentration of glucose increases the activity of SERT, without interfering with its affinity.

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“…Folate & vitamin B12 deficiencies, due to dietary factors, are among the most common deficiencies in India 9 which have been associated with pregnancy-related complications such as NTD. With the mandatory fortification of food with folic acid by USFDA in 1996, the incidence of folate deficiency has become rare 10 . In India, the prevalence of B12 deficiency is high in the reproductive age group due to habits of vegetarian diet and lower social and economic status 9 .…”

Section: Introductionmentioning

confidence: 99%

Effect of imbalance in folate and vitamin B12 in maternal/parental diet on global methylation and regulatory miRNAs

Mahajan

Sapehia

Thakur

et al. 2019

Sci Rep

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DNA methylation, a central component of the epigenetic network is altered in response to nutritional influences. In one-carbon cycle, folate acts as a one-carbon carrier and vitamin B12 acts as co-factor for the enzyme methionine synthase. Both folate and vitamin B12 are the important regulators of DNA methylation which play an important role in development in early life. Previous studies carried out in this regard have shown the individual effects of these vitamins but recently the focus has been to study the combined effects of both the vitamins during pregnancy. Therefore, this study was planned to elucidate the effect of the altered dietary ratio of folate and B12 on the expression of transporters, related miRNAs and DNA methylation in C57BL/6 mice. Female mice were fed diets with 9 combinations of folate and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks post-weaning. Maternal and fetal (F2) tissues were collected at day 20 of gestation. Deficient state of folate led to an increase in the expression of folate transporters in both F1 and F2 generations, however, B12 deficiency (BDFN) also led to an increase in the expression in both the generations. B12 transporters/proteins were found to be increased with B12 deficiency in F1 and F2 generations except for TC-II in the kidney which was found to be decreased in the F1 generation. miR-483 was found to be increased with all conditions of folate and B12 in both F1 and F2 generations, however, deficient conditions of B12 led to an increase in the expression of miR-221 in both F1 and F2 generations. The level of miR-133 was found to be increased in BDFN group in F1 generation however; in F2 generation the change in expression was tissue and sex-specific. Global DNA methylation was decreased with deficiency of both folate and B12 in maternal tissues (F1) but increased with folate deficiency in placenta (F1) and under all conditions in fetal tissues (F2). DNA methyltransferases were overall found to be increased with deficiency of folate and B12 in both F1 and F2 generations. Results suggest that the dietary ratio of folate and B12 resulted in altered expression of transporters, miRNAs, and genomic DNA methylation in association with DNMTs.

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Absorption of folate by Caco-2 cells is not affected by high glucose concentration

Cited by 12 publications

References 25 publications

Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco‐2 cells

Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco‐2 cells

The effect of high glucose on SERT, the human plasmalemmal serotonin transporter

Effect of imbalance in folate and vitamin B12 in maternal/parental diet on global methylation and regulatory miRNAs

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