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

H. C. Haspel, K. N. Stephenson, T. Davies-Hill, A. El-Barbary, J. F. Lobo, R. L. Croxen, W. Mougrabi, E. M. Koehler-Stec, J. D. Fenstermacher, Ian Simpson

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 ~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.

Original languageEnglish (US)
Pages (from-to)45-53
Number of pages9
JournalJournal of Membrane Biology
Volume169
Issue number1
DOIs
StatePublished - May 17 1999

Fingerprint

Barbiturates
Facilitative Glucose Transport Proteins
Protein Isoforms
Glucose
Halogenated Hydrocarbons
Deoxyglucose
Pentobarbital
Inhalation Anesthetics
Blood-Brain Barrier
Adipocytes
Solubility
Inhibitory Concentration 50
Anesthetics
Cultured Cells
Ethanol
Fibroblasts
Erythrocytes
Fluorescence
Pharmacology
Insulin

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Cell Biology
  • Physiology

Cite this

Haspel, H. C. ; Stephenson, K. N. ; Davies-Hill, T. ; El-Barbary, A. ; Lobo, J. F. ; Croxen, R. L. ; Mougrabi, W. ; Koehler-Stec, E. M. ; Fenstermacher, J. D. ; Simpson, Ian. / Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective. In: Journal of Membrane Biology. 1999 ; Vol. 169, No. 1. pp. 45-53.
@article{68ab5ef9a7574c4dbc4af1cb5c93b345,
title = "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 ~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.",
author = "Haspel, {H. C.} and Stephenson, {K. N.} and T. Davies-Hill and A. El-Barbary and Lobo, {J. F.} and Croxen, {R. L.} and W. Mougrabi and Koehler-Stec, {E. M.} and Fenstermacher, {J. D.} and Ian Simpson",
year = "1999",
month = "5",
day = "17",
doi = "10.1007/PL00005900",
language = "English (US)",
volume = "169",
pages = "45--53",
journal = "Journal of Membrane Biology",
issn = "0022-2631",
publisher = "Springer New York",
number = "1",

}

Haspel, HC, Stephenson, KN, Davies-Hill, T, El-Barbary, A, Lobo, JF, Croxen, RL, Mougrabi, W, Koehler-Stec, EM, Fenstermacher, JD & Simpson, I 1999, 'Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective', Journal of Membrane Biology, vol. 169, no. 1, pp. 45-53. https://doi.org/10.1007/PL00005900

Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective. / Haspel, H. C.; Stephenson, K. N.; Davies-Hill, T.; El-Barbary, A.; Lobo, J. F.; Croxen, R. L.; Mougrabi, W.; Koehler-Stec, E. M.; Fenstermacher, J. D.; Simpson, Ian.

In: Journal of Membrane Biology, Vol. 169, No. 1, 17.05.1999, p. 45-53.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective

AU - Haspel, H. C.

AU - Stephenson, K. N.

AU - Davies-Hill, T.

AU - El-Barbary, A.

AU - Lobo, J. F.

AU - Croxen, R. L.

AU - Mougrabi, W.

AU - Koehler-Stec, E. M.

AU - Fenstermacher, J. D.

AU - Simpson, Ian

PY - 1999/5/17

Y1 - 1999/5/17

N2 - 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 ~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.

AB - 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 ~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.

UR - http://www.scopus.com/inward/record.url?scp=0032951946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032951946&partnerID=8YFLogxK

U2 - 10.1007/PL00005900

DO - 10.1007/PL00005900

M3 - Article

VL - 169

SP - 45

EP - 53

JO - Journal of Membrane Biology

JF - Journal of Membrane Biology

SN - 0022-2631

IS - 1

ER -