A phosphorylated phloretin derivative. Synthesis and effect on intestinal Na+-dependent phosphate absorption

Abstract

2′-Phosphophloretin (2′-PP), a phosphorylated derivative of the plant chalcone, was synthesized. The effect of 2′-PP, on Na+-dependent phosphate uptake into intestinal brush-border membrane vesicles (BBMV) isolated from rabbit and rat duodenum and jejunum was examined. 2′-PP decreased Na+-dependent phosphate uptake into rabbit BBMV with an IC50 of 55 nM and into rat BBMV with an IC50 of 58 nM. 2′-PP did not affect Na+-dependent glucose, Na+-dependent sulfate, or Na+-dependent alanine uptake by rabbit intestinal BBMVs. 2′-PP inhibition of rabbit intestinal BBMV Na+-dependent phosphate uptake was sensitive to external phosphate concentration, suggesting that 2′-PP inhibition of Na+-dependent phosphate uptake was competitive with respect to phosphate. Binding of [3H]2′-PP to rabbit intestinal BBMV was examined. Binding of [3H]2′-PP was Na+-dependent with a K 0.5 for Na+(Na+concentration for 50% 2′-PP binding) of 30 mM. The apparent K s for Na+-dependent [3H]2′-PP binding to rabbit BBMVs was 58 nM in agreement with the IC50 for 2′-PP inhibition of Na+-dependent phosphate uptake. These results indicate that 2′-PP bound to rabbit or rat intestinal BBMV Na+-phosphate cotransporter and inhibited Na+-dependent phosphate uptake. In rats treated with 2′-PP by daily gavage, the effect of 2′-PP on serum phosphate, serum glucose, and serum calcium was examined. In a concentration-dependent manner, 2′-PP reduced serum phosphate by 45% 1 wk after starting treatment. 2′-PP did not alter serum calcium or serum glucose. The apparent IC50 for 2′-PP in vivo was 3 μM.