Enzyme and receptor antagonists for preventing toxicity from the gamma-hydroxybutyric acid precursor 1,4-butanediol in CD-1 mice.
1,4-Butanediol (1,4-BD), the diol alcohol precursor of gamma-hydroxybutyric acid (GHB), undergoes in vivo enzymatic biotransformation to GHB by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. The subsequent metabolite, GHB, is pharmacologically active at GABA(B) and GHB receptors. GHB can be metabolized in vivo to gamma-aminobutyric acid (GABA) and trans-4-hydroxycrotonic acid (T-HCA), which are also pharmacologically active at GABA(B) receptors and GHB receptors, respectively. Therefore, we speculate that 1,4-BD overdose toxicity can be prevented or attenuated with the ADH enzyme inhibitor 4-methylpyrazole (4-MP) as well as with CGP-35348 and NCS-382, novel high-affinity receptor antagonists of GABA(B) receptors and GHB receptors, respectively. In our murine model of acute 1,4-BD overdose, pretreatment of CD-1 mice with 4-MP significantly attenuated increases in blood GHB concentrations and prevented loss of the righting reflex and failure of the rotarod test. Also, pretreatment with CGP-35348 and its combination with NCS-382 significantly decreased the duration of failure for the rotarod test and the percentage of animals failing the rotarod test, respectively. However, pretreatment of CD-1 mice with NCS-382 alone produced prolonged failure of the rotarod test, an unexpected synergistic effect with 1,4-BD and presumably GHB, which has not previously been demonstrated.
Quang
Lawrence S
LS
Division of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. lawrence.quang@tch.harvard.edu
Desai
Malhar C
MC
Kraner
James C
JC
Shannon
Michael W
MW
Woolf
Alan D
AD
Maher
Timothy J
TJ
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001711:Biotransformation; D002072:Butylene Glycols / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000077604:Fomepizole; D008297:Male; D051379:Mice; D011187:Posture; D011720:Pyrazoles / Q000494:pharmacology*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000097:blood*
D000931:Antidotes; D002072:Butylene Glycols; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D005680:gamma-Aminobutyric Acid; C039681:1,4-butanediol; D000077604:Fomepizole