Trans-Hydroxyl Group Configuration on Carbons 2 and 3 of Glucose: Responsible for Acute Inhibition of myo-Inositol Transport?

Cultured neuroblastoma, cerebral μvessel endothelial, and retinoblastoma cells were used to examine the mechanism of acute inhibition by D-glucose of myo-inositol uptake. Acute exposure of the cells to 30 mM D-glucose caused a significant decrease in Na⁺-dependent myo-inositol uptake in all three cell types. The effect of D-glucose to acutely inhibit myo-inositol uptake was dependent on the extracellular glucose concentration and was not reversed by sorbinil. 2-Deoxy-D-glucose (30 mM), 3-O-methyl-D-glucose (30 mM), and cytochalasin B (100 μM) did not acutely inhibit myo-inositol uptake. These data suggest that the hydroxyl groups on carbons 2 and 3 of D-glucose, which in a Haworth projection appear trans to each other, are important for inhibitory activity. Other monosaccharides (30 mM) having a similar 2,3-trans–diol configuration, L-glucose, D- and L-fucose, D- and L-galactose, D- and L-xylose, and D-arabinose, all to varying degrees significantly inhibited myo-inositol uptake. In all cases, the L-isomers were more potent inhibitors of myo-inositol uptake than the corresponding D-isomers. Monosaccharides (30 mM) having hydroxyl groups on carbons 2 and 3 in a cis configuration, D-mannose, L-rhamnose, D-allose, and D-ribose, did not acutely inhibit myo-inositol uptake. Replacing the hydroxyl group with a fluorine on carbons 2 or 3 of D-glucose negated its inhibitory activity of myo-inositol uptake. In contrast, replacing the hydroxyl group with a fluorine on carbon 6 of D-glucose did not block its inhibition of myo-inositol uptake. 4-Fluoro-4-deoxy-D-glucose did not block myo-inositol uptake by neuroblastoma cells but was almost as effective as D-glucose in inhibiting myo-inositol uptake by cerebral microvessel endothelial and retinoblastoma cells. These data suggest that the trans diol on carbons 2 and 3 of D-glucose is necessary for 4-Fluoro-4-deoxy-D-glucose did not block myo-inositol uptake by neuroblastoma cells but was almost as effective as D-glucose in inhibiting myo-inositol uptake by cerebral microvessel endothelial and retinoblastoma cells. These data suggest that the trans diol on carbons 2 and 3 of D-glucose is necessary for this site.