GENISTEIN IS A NATURAL INHIBITOR OF HEXOSE AND DEHYDROASCORBIC ACID TRANSPORT THROUGH THE GLUCOSE-TRANSPORTER, GLUT1

Genistein is a dietary-derived plant product that inhibits the activit y of protein-tyrosine kinases, We show here that it is a potent inhibi tor of the mammalian facilitative hexose transporter GLUT1, In human H L-60 cells, which express GLUT1, genistein inhibited the transport of dehydroascorbic acid, deoxyglucose, and methylglucose in a dose-depend ent manner, Transport was not affected by daidzein, an inactive genist ein analog that does not inhibit protein-tyrosine kinase activity, or by the general protein kinase inhibitor staurosporine, Genistein inhib ited the uptake of deoxyglucose and dehydroascorbic acid in Chinese ha mster ovary (CHO) cells overexpressing GLUT1 in a similar dose-depende nt manner, Genistein also inhibited the uptake of deoxyglucose in huma n erythrocytes indicating that its effect on glucose transporter funct ion is cell-independent, The inhibitory action of genistein on transpo rt was instantaneous, with no additional effect observed in cells prei ncubated with it for various periods of time, Genistein did not alter the uptake of leucine by HL-60 cells, indicating that its inhibitory e ffect was specific for the glucose transporters, The inhibitory effect of genistein was of the competitive type, with a K-i of approximately 12 mu M for inhibition of the transport of both methylglucose and deo xyglucose. Binding studies showed that genistein inhibited glucose-dis placeable binding of cytochalasin B to GLUT1 in erythrocyte ghosts in a competitive manner, with a K-i of 7 mu M. These data indicate that g enistein inhibits the transport of dehydroascorbic acid and hexoses by directly interacting with the hexose transporter GLUT1 and interferin g with its transport activity, rather than as a consequence of its kno wn ability to inhibit protein-tyrosine kinases, These observations ind icate that some of the many effects of genistein on cellular physiolog y may be related to its ability to disrupt the normal cellular flux of substrates through GLUT1, a hexose transporter universally expressed in cells, and is responsible for the basal uptake of glucose.