When diabetic rats were administered glucose with quercetin, hyperglycemia was significantly decreased compared with administration of glucose alone. Quercetin also significantly decreased ascorbate absorption in normal rats given ascorbate plus quercetin compared with rats given ascorbate alone. Quercetin was a specific transport inhibitor, because it did not inhibit intestinal sugar transporters GLUT5 and SGLT1 that were injected and expressed in Xenopus oocytes. Quercetin inhibited but was not transported by SVCT1(h). Considered together, these data show that flavonoids modulate vitamin C and glucose transport by their respective intestinal transporters and suggest a new function for flavonoids.Flavonoids are polyphenols that are widely distributed in plant foods and ingested by humans. Flavonoids are subdivided into six structural classes, flavones, flavonols, flavanones, isoflavones, anthocyanidins, and catechins. Although some flavonoids have been proposed to be antioxidants, flavonoid function in vivo is uncertain (1, 2).The flavonoid-like compound phloretin was utilized more than four decades ago to inhibit sodium-independent glucose transport (3). Structural analogs of phloretin from the flavonoid classes of flavanones and flavones inhibited sodiumindependent glucose efflux from intestinal cells but not sodiumdependent glucose uptake (4). Because glucose is structurally similar to ascorbic acid (ascorbate, vitamin C) and especially to its oxidized product dehydroascorbic acid (5-7), more recent reports describe effects of flavonoids on ascorbate, dehydroascorbic acid, and glucose transport. The flavonol quercetin and the isoflavone genistein at relatively high concentrations of 100 M decreased ascorbate transport in three intestinal cell lines (8). The isoflavone genistein but not the related isoflavone daidzein inhibited glucose and dehydroascorbic acid transport in leukemic (HL-60) cells (9). Inhibition of glucose transport by genistein was competitive and occurred in cells overexpressing GLUT1.
Dehydroascorbic acid (DHA), the first stable oxidation product of vitamin C, was transported by GLUT1 and GLUT3 in Xenopus laevis oocytes with transport rates similar to that of 2-deoxyglucose (2-DG), but due to inherent difficulties with GLUT4 expression in oocytes it was uncertain whether GLUT4 transported DHA (Rumsey, S. C. , Kwon, O., Xu, G. W., Burant, C. F., Simpson, I., and Levine, M. (1997) J. Biol. Chem. 272, 18982-18989). We therefore studied DHA and 2-DG transport in rat adipocytes, which express GLUT4. Without insulin, rat adipocytes transported 2-DG 2-3-fold faster than DHA. Preincubation with insulin (0.67 micrometer) increased transport of each substrate similarly: 7-10-fold for 2-DG and 6-8-fold for DHA. Because intracellular reduction of DHA in adipocytes was complete before and after insulin stimulation, increased transport of DHA was not explained by increased internal reduction of DHA to ascorbate. To determine apparent transport kinetics of GLUT4 for DHA, GLUT4 expression in Xenopus oocytes was reexamined. Preincubation of oocytes for >4 h with insulin (1 micrometer) augmented GLUT4 transport of 2-DG and DHA by up to 5-fold. Transport of both substrates was inhibited by cytochalasin B and displayed saturable kinetics. GLUT4 had a higher apparent transport affinity (K(m) of 0.98 versus 5.2 mm) and lower maximal transport rate (V(max) of 66 versus 880 pmol/oocyte/10 min) for DHA compared with 2-DG. The lower transport rate for DHA could not be explained by binding differences at the outer membrane face, as shown by inhibition with ethylidene glucose, or by transporter trans-activation and therefore was probably due to substrate-specific differences in transporter/substrate translocation or release. These novel data indicate that the insulin-sensitive transporter GLUT4 transports DHA in both rat adipocytes and Xenopus oocytes. Alterations of this mechanism in diabetes could have clinical implications for ascorbate utilization.
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