Effects of Barbiturates on Facilitative Glucose Transporters are Pharmacologically Specific and Isoform Selective

Abstract

Barbiturates inhibit GLUT-1-mediated glucose transport across the blood-brain barrier, in cultured mammalian cells, and in human erythrocytes. Barbiturates also interact directly with GLUT-1. The hypotheses that this inhibition of glucose transport is (i) selective, preferring barbiturates over halogenated hydrocarbon inhalation anesthetics, and (ii) specific, favoring some GLUT-# isoforms over others were tested. Several oxy- and thio-barbiturates inhibited [3H]-2-deoxyglucose uptake by GLUT-1 expressing murine fibroblasts with IC50s of 0.2-2.9 mm. Inhibition of GLUT-1 by barbiturates correlates with their overall lipid solubility and pharmacology, and requires hydrophobic side chains on the core barbiturate structure. In contrast, several halogenated hydrocarbons and ethanol (all </=10 mm) do not significantly inhibit glucose transport. The interaction of these three classes of anesthetics with purified GLUT-1 was evaluated by quenching of intrinsic protein fluorescence and displayed similar specificities and characteristics. The ability of barbiturates to inhibit other facilitative glucose transporters was determined in cell types expressing predominantly one isoform. Pentobarbital inhibits [3H]-2-deoxyglucose and [14C]-3-O-methyl-glucose uptake in cells expressing GLUT-1, GLUT-2, and GLUT-3 with IC50s of approximately 1 mm. In contrast, GLUT-4 expressed in insulin-stimulated rat adipocytes was much less sensitive than the other isoforms to inhibition by pentobarbital (IC50 of >10 mm). Thus, barbiturates selectively inhibit glucose transport by some, but not all, facilitative glucose transporter isoforms.

Effect of Deep Pentobarbital Anesthesia on Neurotransmitter Metabolism in Vivo: On the Correlation of Total Glucose Consumption with Glutamatergic Action

“…In this analysis, it was assumed that the apparent Michaelis-Menten constant for glucose transport, K t , and the maximal apparent glucose transport rate, T max , were not affected by the deep pentobarbital anesthesia. A recent report suggested that the transport affinity for glucose may change under pentobarbital anesthesia in cultured cells and erythrocytes (Haspel et al, 1999). When we allow a fivefold change in the apparent Michaelis-Menten constant K t (K t ranging from 1 to 5 mmol/L), T max /CMR glc was affected by approximately 20%, which did not change the conclusions of this study, namely, that overall glucose metabolism was still considerable.…”

Insulin sensitivity and inhibition by forskolin, dipyridamole and pentobarbital of glucose transport in three L6 muscle cell lines

“…Pentobarbital has been shown to inhibit glucose transport by GLUT1, GLUT2 and GLUT3, more effectively than GLUT4-mediated glucose uptake [9] . Consistent with these observations, we observed a 46% inhibition of basal glucose uptake in L6-GLUT1myc when 1 mmol/L pentobarbital was present in the transport assay (Figure 9(a)).…”

“…Among these small molecules, cytochalasin B is the best known. The diterpene forskolin, pentobarbital, the nucleoside transport inhibitor dipyridamole, and the HIV protease inhibitor, indinavir, also mediate competitive (or noncompetitive) inhibition of glucose transport [8][9][10] . Indinavir is unique in that it can inhibit GLUT4 activity with two orders of magnitude greater affinity compared with GLUT1 in L6 cells [6] .…”

Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations

“…Concentrations are the net result of input and output to a metabolite pool, and either or both processes can affect metabolite level. Interpretive complexity of data is compounded by heterogeneity of TBI type, location, and severity, and by standard-of-care clinical protocols that use drugs for sedation or anesthesia, e.g., barbiturates and propofol, that can inhibit GLUT-1-mediated glucose transport, 27,28 as well as depress brain function, energy demand, blood flow, and metabolic activity, all of which influence metabolite levels.…”