Inhibition of human intestinal brush border membrane vesicle Na+-dependent phosphate uptake by phosphophloretin derivatives

Peerce, Brian E.; Fleming, Rachel; Clarke, Rebecca

doi:10.1016/s0006-291x(02)02974-1

Cited by 21 publications

(14 citation statements)

References 14 publications

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“…The pH dependence of 2Ј-PP inhibition of intestinal Na ϩ -dependent phosphate uptake was consistent with the pH dependence of Na ϩ binding to the cotransporter (10,28,33,41). These results are similar to previous studies (28,34,35). Based on these studies, phloretin derivative sensitivity of NaPi-IIb was 2Ј-PP Ͼ Ͼ PTMP Ն phloretin.…”

Section: Discussionsupporting

confidence: 90%

“…Fractions were assayed for protein (34,36), leucine amino peptidase activity, alkaline phosphatase activity (15), succinate dehydrogenase activity (51), ␥-glutamyl transpeptidase (30), phloridzin-sensitive Na ϩ -dependent [ 3 H]glucose uptake (35), and Na ϩ -K ϩ -ATPase activity (40). Proximal tubule BBMV and distal tubule BBMV enrichments are summarized in Tables 1 and 2.…”

Section: Preparation Of Distal Tubules and Proximal Tubulesmentioning

confidence: 99%

“…In vitro a phosphorylated chalcone 2Ј-phosphophloretin (2Ј-PP) has been reported to specifically inhibit NaPi-IIb in human (35), rat (34), and rabbit (34) intestinal BBM vesicles (BBMV). In vivo 2Ј-PP decreased serum phosphate in aged adult rats (34).…”

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confidence: 99%

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Phosphophloretin sensitivity of rabbit renal NaPi-IIa and NaPi-Ia

Peerce

Clarke

2004

American Journal of Physiology-Renal Physiology

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The effect of phosphorylated phloretins on Na(+)-dependent phosphate uptake into rabbit renal brush-border membrane vesicles (BBMV) was examined. Na(+)-dependent phosphate uptake into isolated rabbit cortex BBMV was sensitive to 2'-phosphophloretin (2'-PP) and 2'-phospho-4',4,6'-trimethoxy phloretin (PTMP) in a dose-dependent and pH-dependent manner. PTMP inhibition of Na(+)-dependent phosphate uptake was maximum at alkali pH, and 2'-PP inhibition of Na(+)-dependent phosphate uptake was maximum at acidic pH. Increasing Na(+) concentrations did not increase PTMP inhibition of renal cortex BBMV Na(+)-dependent phosphate uptake at pH 6. The effect of phosphophloretins on Na(+)-dependent phosphate uptake was examined in BBMV isolated from purified proximal tubules and distal tubules. 2'-PP and PTMP inhibition of Na(+)-dependent phosphate uptake into BBMV isolated from purified proximal tubules was similar to the inhibition seen with BBMV from renal cortex. 2'-PP, but not PTMP, inhibited Na(+)-dependent phosphate uptake into BBMV isolated from purified distal tubules. The pH dependence of inhibition, the absence of PTMP inhibition of Na(+)-dependent phosphate uptake into distal tubule BBMV, and the inhibition of Na(+)-dependent phosphate uptake into distal tubule BBMV suggest that NaPi-Ia is 2'-PP sensitive and NaPi-IIa is PTMP sensitive.

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Section: Discussionsupporting

confidence: 90%

Section: Preparation Of Distal Tubules and Proximal Tubulesmentioning

confidence: 99%

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Phosphophloretin sensitivity of rabbit renal NaPi-IIa and NaPi-Ia

Peerce

Clarke

2004

American Journal of Physiology-Renal Physiology

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“…When given to hemodialysis patients, oral nicotinamide reduced hyperphosphatemia (128), although treatment was associated with significant gastrointestinal side effects that may limit its clinical usefulness. Phosphophloretin, a phosphorylated form of the plant chalcone phloretin, has been shown to be a competitive inhibitor of renal (100) and intestinal sodium-dependent phosphate transport in rabbits (98), rats (98), and humans (99) and to reduce serum phosphate levels in normal (98) and uremic rats (101). Finally, JTP-59557, a triazole derivative, is a noncompetitive inhibitor of phosphate transport across the rat small intestine in vivo, which is probably due to an action on NaPi-IIb (82).…”

Section: Intestinal Phosphate Transport In Crfmentioning

confidence: 99%

Phosphate homeostasis and the renal-gastrointestinal axis

Marks¹,

Debnam²,

Unwin

2010

American Journal of Physiology-Renal Physiology

179

154

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Transport of phosphate across intestinal and renal epithelia is essential for normal phosphate balance, yet we know less about the mechanisms and regulation of intestinal phosphate absorption than we do about phosphate handling by the kidney. Recent studies have provided strong evidence that the sodium-phosphate cotransporter NaPi-IIb is responsible for sodium-dependent phosphate absorption by the small intestine, and it might be that this protein can link changes in dietary phosphate to altered renal phosphate excretion to maintain phosphate balance. Evidence is also emerging that specific regions of the small intestine adapt differently to acute or chronic changes in dietary phosphate load and that phosphatonins inhibit both renal and intestinal phosphate transport. This review summarizes our current understanding of the mechanisms and control of intestinal phosphate absorption and how it may be related to renal phosphate reabsorption; it also considers the ways in which the gut could be targeted to prevent, or limit, hyperphosphatemia in chronic and end-stage renal failure.

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“…These possibly act in a non-competitive manner on NaPi-II proteins as reported for the compound JTP-59557 (Matsuo et al, 2005). A phosphophloretin compound was reported to exhibit inhibition at micromolar concentrations (Peerce et al, 2003) although its efficacy on heterologously expressed SLC34 proteins is unknown.…”

Section: Pharmacologymentioning

confidence: 92%

Phosphate transporters of the SLC20 and SLC34 families

Forster

Hernando

Biber

et al. 2013

Molecular Aspects of Medicine

178

198

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Transport of inorganic phosphate (Pi) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na(+)-dependent, secondary-active cotransporters to transport Pi across cell membranes. The SLC34 proteins are expressed in specific organs important for Pi homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in Pi reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates Pi absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity, regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarizes our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiology and pharmacology. AbstractTransport of inorganic phosphate (P i ) across the plasma membrane is essential for normal cellular function. Members of two families of SLC proteins (SLC20 and SLC34) act as Na + -dependent, secondary-active cotransporters to transport P i across cell membranes. The SLC34 proteins are expressed in specific organs important for P i homeostasis: NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) fulfill essential roles in P i reabsorption in the kidney proximal tubule and NaPi-IIb (SLC34A2) mediates P i absorption in the gut. The SLC20 proteins, PiT-1 (SLC20A1), PiT-2 (SLC20A2) are expressed ubiquitously in all tissues and although generally considered as "housekeeping" transport proteins, the discovery of tissue-specific activity,regulatory pathways and gene-related pathophysiologies, is redefining their importance. This review summarises our current knowledge of SLC20 and SLC34 proteins in terms of their basic molecular characteristics, physiological roles, known pathophysiologies and pharmacology.3

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Inhibition of human intestinal brush border membrane vesicle Na+-dependent phosphate uptake by phosphophloretin derivatives

Cited by 21 publications

References 14 publications

Phosphophloretin sensitivity of rabbit renal NaPi-IIa and NaPi-Ia

Phosphophloretin sensitivity of rabbit renal NaPi-IIa and NaPi-Ia

Phosphate homeostasis and the renal-gastrointestinal axis

Phosphate transporters of the SLC20 and SLC34 families

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