Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective

Barbiturates inhibit GLUT-1-mediated glucose transport across the blood-bra in barrier, in cultured mammalian cells, and in human erythrocytes. Barbitu rates also interact directly with GLUT-1. The hypotheses that this inhibiti on of glucose transport is (i) selective, preferring barbiturates over halo genated hydrocarbon inhalation anesthetics, and (ii) specific, favoring som e GLUT-# isoforms over others were tested. Several oxy- and thio-barbiturat es inhibited [H-3]-2-deoxyglucose uptake by GLUT-1 expressing murine fibrob lasts with IC(50)s of 0.2-2.9 mM. Inhibition of GLUT-1 by barbiturates corr elates with their overall lipid solubility and pharmacology, and requires h ydrophobic side chains on the core barbiturate structure. In contrast, seve ral halogenated hydrocarbons and ethanol (all less than or equal to 10 mM) do not significantly inhibit glucose transport. The interaction of these th ree classes of anesthetics with purified GLUT-1 was evaluated by quenching of intrinsic protein fluorescence and displayed similar specificities and c haracteristics. The ability of barbiturates to inhibit other facilitative g lucose transporters was determined in cell types expressing predominantly o ne isoform. Pentobarbital inhibits [H-3]-2-deoxyglucose and [C-14]-3-O-meth yl-glucose uptake in cells expressing GLUT-1, GLUT-2, and GLUT-3 with IC(50 )s of similar to 1 mM. In contrast, GLUT-4 expressed in insulin-stimulated rat adipocytes was much less sensitive than the other isoforms to inhibitio n by pentobarbital (IC50 of >10 mM). Thus, barbiturates selectively inhibit glucose transport by some, but not all, facilitative glucose transporter i soforms.