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A phosphorylated phloretin derivative. Synthesis and effect on intestinal Na(+)-dependent phosphate absorption
Brian E Peerce1, Rebecca Clarke
1Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-0641, USA. BPeerce@UTMB.edu
American Journal of Physiology. Gastrointestinal and Liver Physiology
|September 12, 2002
Summary
2'-Phosphophloretin (2'-PP), a plant chalcone derivative, effectively inhibits sodium-dependent phosphate uptake in the intestines. This compound also lowers serum phosphate levels in rats, demonstrating its potential as a therapeutic agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Intestinal phosphate absorption is a critical physiological process regulated by sodium-dependent cotransporters.
- Understanding the molecular mechanisms and potential modulators of phosphate transport is essential for metabolic health.
- 2 -Phosphophloretin (2 -PP), a novel phosphorylated chalcone derivative, was synthesized for investigation.
Purpose of the Study:
- To investigate the effect of 2 -PP on sodium-dependent phosphate uptake in intestinal brush-border membrane vesicles (BBMVs).
- To determine the inhibitory potential and mechanism of 2 -PP on intestinal phosphate transport.
- To evaluate the in vivo effects of 2 -PP on serum phosphate, glucose, and calcium levels in rats.
Main Methods:
- Isolation of intestinal brush-border membrane vesicles (BBMVs) from rabbit and rat duodenum and jejunum.
- Measurement of Na(+)-dependent phosphate uptake in BBMVs using radiolabeled phosphate.
- Assessment of 2 -PP binding to BBMVs and its effect on other nutrient transport systems (glucose, alanine, sulfate).
- In vivo studies involving daily gavage administration of 2 -PP to rats and subsequent serum analysis.
Main Results:
- 2 -PP significantly inhibited Na(+)-dependent phosphate uptake in both rabbit (IC(50) = 55 nM) and rat (IC(50) = 58 nM) BBMVs.
- The inhibition was specific to phosphate, as 2 -PP did not affect Na(+)-dependent glucose, sulfate, or alanine uptake.
- Inhibition was competitive with respect to phosphate, and 2 -PP binding to BBMVs was Na(+)-dependent (K(0.5) for Na(+) = 30 mM).
- In vivo, 2 -PP administration reduced serum phosphate levels by 45% in a concentration-dependent manner (in vivo IC(50) = 3 µM) without affecting serum calcium or glucose.
Conclusions:
- 2 -PP acts as a potent inhibitor of the intestinal Na(+)-phosphate cotransporter in both rabbits and rats.
- The findings suggest that 2 -PP has the potential to modulate phosphate homeostasis in vivo.
- 2 -PP represents a promising candidate for further research into the therapeutic management of phosphate-related disorders.