Folate Transport Proteins Mediate the Bidirectional Transport of 5-Methyltetrahydrofolate in Cultured Human Proximal Tubule Cells , ,

Morshed, Khandoker M.; Ross, Donna M.; McMartin, Kenneth E.

doi:10.1093/jn/127.6.1137

Cited by 46 publications

(28 citation statements)

References 29 publications

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“…Hence, it may, theoretically, also contribute to an absorptive transport if coupled to a suitable importer at the apical face. Such a situation has been suggested for its low affinity substrate folate (Morshed et al 1997). At least in the MDCK model, expression of rRfc-1 clearly increases the b-a flux of unlabeled Mtx and FMTX.…”

Section: Discussionmentioning

confidence: 79%

Rat reduced-folate carrier-1 is localized basolaterally in MDCK kidney epithelial cells and contributes to the secretory transport of methotrexate and fluoresceinated methotrexate

Kneuer

Honscha

2005

Cell Tissue Res

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The reduced-folate carrier (Rfc-1), previously also called methotrexate carrier-1 (MTX-1), was recently identified as accounting for approximately 30% of the methotrexate (Mtx) uptake into rat kidney slices. The localization of the carrier and its contribution to secretory or reabsorptive flux of the drug was therefore evaluated in polarized epithelial layers of Madin Darby canine kidney (MDCK) cells. Confocal laser scanning microscopy revealed that the HA-epitope-tagged protein was sorted to the basolateral side. In flux assays, the basolateral-to-apical transport of fluoresceinated methotrexate (FMTX) was two-fold higher than in the apical-to-basolateral direction across rat Rfc-1 transfected, but not mock-transfected, monolayers. The same observation was made for unlabeled Mtx. This secretory transport of FMTX was inhibited by an excess of 1 mM Mtx and was saturable and temperature-dependent. No differences in directional flux were observed for the pure fluorescein label. Removal of sodium resulted in a marked decrease of directional FMTX flux. The pH profile of the active transport component showed a trough around 6.5 and a maximum at acidic pH, as reported for uptake into Rfc-1-expressing cells. Thus, rat Rfc-1 is sorted to the basolateral side in polarized MDCK epithelial cells and mediates the secretion of Mtx, probably in co-operation with efflux proteins, such as multidrug resistance associated proteins, which are also expressed in these cells.

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Section: Discussionmentioning

confidence: 79%

Rat reduced-folate carrier-1 is localized basolaterally in MDCK kidney epithelial cells and contributes to the secretory transport of methotrexate and fluoresceinated methotrexate

Kneuer

Honscha

2005

Cell Tissue Res

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“…The kidney expresses both FR and RFC (17,41,42). Proximal tubule cell culture studies have implicated RFC in apical transport of MTHF (43,44), and RFC has been located by immunocytochemistry to basolateral membranes in kidney tubules (17). Thus, RFC may be involved in apical folate transport at high folate concentrations or in the cellular exit of reabsorbed folate.…”

Section: Discussionmentioning

confidence: 99%

Renal Tubular Reabsorption of Folate Mediated by Folate Binding Protein 1

Birn¹,

Spiegelstein²,

Christensen³

et al. 2005

Journal of the American Society of Nephrology

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Renal tubular reabsorption of filtered folate is essential for the conservation and normal homeostasis of this important vitamin. Different molecular mechanisms have been implicated in epithelial folate transport, including folate receptors. Defective expression or antibody inactivation of these is associated with embryonic defects also correlated with low folate intake; however, their contribution to renal tubular folate reabsorption has not been established. With the use of targeted inactivation of the folate binding protein 1 (folbp1) and folate binding protein 2 (folbp2) genes in mice, the role of folate receptors in renal epithelial folate reabsorption was evaluated during low and normal folate intake. Inactivation of folbp1 was associated with (1) loss of 3 H-folic acid binding to crude kidney membranes, (2) increase in renal folate clearance, and (3) increase in urinary excretion and decrease in renal uptake of injected 3 H-methyltetrahydrofolate. No changes in renal folate handling were observed as a result of folbp2 inactivation. Thus, folbp1 is essential for normal renal tubular folate reabsorption, preventing excessive urinary folate loss. Folbp1 is heavily expressed in choroid plexus, yolk sac, and placenta, supporting a role of folbp1 in folate transport in other tissues. The greatest significance of folbp1 for renal folate uptake was observed at conditions of low folate intake, providing a possible explanation for the ability of folate supplementation to prevent developmental defects associated with folbp1 inactivation.

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“…administered FA conjugates (14,47,49,50). Overall, the function of kidney FRs seems to be to capture FAs, or drug conjugates thereof, in the urinary filtrate and to transcytose them back into the blood (47,48,51). Supporting this hypothesis are the observations that (a) analyses of blood from animals after i.v.…”

Section: Cancer Researchmentioning

confidence: 98%

Folate Receptor–Specific Antitumor Activity of EC131, a Folate-Maytansinoid Conjugate

et al. 2007

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EC131, a new folate receptor (FR)-targeted drug conjugate, was prepared by covalently attaching the vitamin folic acid (FA) to a potent microtubule-inhibiting agent, maytansinoid DM1, via an intramolecular disulfide bond. When tested on cells in culture, EC131 was found to retain high affinity for FRpositive cells and to provide FR-specific cytotoxicity with an IC 50 in the low nanomolar range. The activity of EC131 was completely blocked in the presence of an excess of free FA, and no activity was detected against FR-negative cells. When evaluated against s.c. FR-positive M109 tumors in BALB/c mice, EC131 showed marked antitumor efficacy. Furthermore, this therapeutic effect occurred in the apparent absence of weight loss or noticeable organ tissue degeneration. In contrast, no significant antitumor activity was observed in EC131-treated animals that were codosed with an excess of FA, thus demonstrating the targeted specificity of the in vivo activity. EC131 also showed marked antitumor activity against FR-positive human KB tumors, but not against FR-negative A549 tumors, in nude mice with no evidence of systemic toxicity during or after the therapy. In contrast, therapy with the free maytansinoid drug (in the form of DM1-S-Me) proved not to be effective against the KB model when administered at its maximum tolerated dose (MTD). Taken together, these results indicate that EC131 is a highly potent agent capable of producing therapeutic benefit in murine tumor models at sub-MTD levels. [Cancer Res 2007;67(13):6376-82]

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Folate Transport Proteins Mediate the Bidirectional Transport of 5-Methyltetrahydrofolate in Cultured Human Proximal Tubule Cells , ,

Cited by 46 publications

References 29 publications

Rat reduced-folate carrier-1 is localized basolaterally in MDCK kidney epithelial cells and contributes to the secretory transport of methotrexate and fluoresceinated methotrexate

Rat reduced-folate carrier-1 is localized basolaterally in MDCK kidney epithelial cells and contributes to the secretory transport of methotrexate and fluoresceinated methotrexate

Renal Tubular Reabsorption of Folate Mediated by Folate Binding Protein 1

Folate Receptor–Specific Antitumor Activity of EC131, a Folate-Maytansinoid Conjugate

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