Tmic
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Record Information
Version2.0
Creation Date2014-08-29 06:11:02 UTC
Update Date2018-03-21 17:46:12 UTC
Accession NumberT3D4269
Identification
Common Name4-Hydroxybutyric acid
ClassSmall Molecule
Description4-Hydroxybutyric acid (also known as gamma-hydroxybutyrate or GHB) is a precursor and a metabolite of gamma-aminobutyric acid (GABA). GHB acts as a central nervous system (CNS) neuromodulator, mediating its effects through GABA and GHB-specific receptors, or by affecting dopamine transmission (PMID: 16620539). GHB occurs naturally in all mammals, but its function remains unknown. GHB is labeled as an illegal drug in most countries, but it also is used as a legal drug (Xyrem) in patients with narcolepsy. It is used illegally (under the street names juice, liquid ecstasy, or G) as an intoxicant for increasing athletic performance and as a date rape drug. In high doses, GHB inhibits the CNS, inducing sleep and inhibiting the respiratory drive. In lower doses, its euphoriant effect predominates (PMID: 17658710). When present in sufficiently high levels, 4-hydroxybutyric acid can act as an acidogen, a neurotoxin, and a metabotoxin. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A neurotoxin is a compound that adversely affects neural cells and tissues. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of 4-hydroxybutyric acid are associated with two inborn errors of metabolism: glutaric aciduria II and succinic semialdehyde dehydrogenase deficiency (SSADH). SSADH deficiency leads to a 30-fold increase of GHB and a 2-4 fold increase of GABA in the brains of patients with SSADH deficiency as compared to normal brain concentrations of the compounds. As an acidogen, 4-hydroxybutyric acid is an organic acid, and abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain, and other tissues lead to general metabolic acidosis. Acidosis typically occurs when arterial pH falls below 7.35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These can progress to heart abnormalities, kidney abnormalities, liver damage, seizures, coma, and possibly death. Many affected children with organic acidemias experience intellectual disability or delayed development. These are also the characteristic symptoms of the untreated IEMs mentioned above. Particularly for SSADH deficiency, the most common features observed include developmental delay, hypotonia, and intellectual disability. Nearly half of patients exhibit ataxia, seizures, behaviour problems, and hyporeflexia. In adults, acidosis or acidemia is characterized by headaches, confusion, feeling tired, tremors, sleepiness, and seizures. As a neurotoxin, GHB appears to affect both GABA (a neurotransmitter) signaling and glutamate signaling (another neurotransmitter). Glutamine metabolism may also play a role in the pathophysiology of excessive levels of GHB. High levels of GHB have been shown to depress both the NMDA and AMPA/kainite receptor-mediated functions and may also alter glutamatergic excitatory synaptic transmission as well.
Compound Type
  • Animal Toxin
  • Drug
  • Food Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
Chemical Structure
Thumb
Synonyms
Synonym
3-carboxypropoxy acid
4-Hydroxy-Butanoate
4-Hydroxy-Butanoic acid
4-Hydroxy-butyric acid
4-Hydroxybutanoate
4-Hydroxybutanoic acid
4-Hydroxybutyrate
4-Hydroxybutyrate sodium
4-Hydroxybutyric acid monosodium salt
gamma-Hydroxy butyrate
gamma-Hydroxy sodium butyrate
gamma-Hydroxybutyrate
gamma-Hydroxybutyrate sodium
gamma-Hydroxybutyric acid
GHB
Hydroxybutyric acid
Monosodium salt
oxy-n-butyric acid
Oxybate sodium
Sodium gamma-hydroxybutyrate
Sodium gamma-oxybutyrate
Sodium oxybate
Xyrem
γ-Hydroxybutyric acid
Chemical FormulaC4H8O3
Average Molecular Mass104.105 g/mol
Monoisotopic Mass104.047 g/mol
CAS Registry Number591-81-1
IUPAC Name4-hydroxybutanoic acid
Traditional Namegamma hydroxybutyric acid
SMILESOCCCC(O)=O
InChI IdentifierInChI=1S/C4H8O3/c5-3-1-2-4(6)7/h5H,1-3H2,(H,6,7)
InChI KeyInChIKey=SJZRECIVHVDYJC-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as hydroxy fatty acids. These are fatty acids in which the chain bears a hydroxyl group.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acids and conjugates
Direct ParentHydroxy fatty acids
Alternative Parents
Substituents
  • Short-chain hydroxy acid
  • Hydroxy fatty acid
  • Straight chain fatty acid
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Organic oxygen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginEndogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
Pathways
NameSMPDB LinkKEGG Link
4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase DeficiencySMP00243 Not Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
LogPNot Available
Predicted Properties
PropertyValueSource
Water Solubility494 g/LALOGPS
logP-0.63ALOGPS
logP-0.51ChemAxon
logS0.68ALOGPS
pKa (Strongest Acidic)4.44ChemAxon
pKa (Strongest Basic)-2.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.53 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity23.8 m³·mol⁻¹ChemAxon
Polarizability10.17 ųChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
GC-MSGC-MS Spectrum - GC-MS (2 TMS)splash10-0159-2920000000-131f94186a93d0aa315dView in MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0159-2920000000-131f94186a93d0aa315dView in MoNA
GC-MSGC-MS Spectrum - GC-EI-TOF (Non-derivatized)splash10-0002-0910000000-7240955b6b16291cf793View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a5c-9000000000-915d32c0dbd6e6d19a55View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-00di-9610000000-52e5254f6eba257ad184View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-9100000000-80636ab7e3cb47d4d58fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-05n4-9000000000-71899633e269029ab7f9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9000000000-910235f5bc92bcca7469View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-8900000000-5890f0a527dd16d9ac75View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0k9i-9200000000-241210fedf9304168090View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4l-9000000000-21d09118dfcfcb093f8dView in MoNA
MSMass Spectrum (Electron Ionization)splash10-0006-9000000000-d55d971a361b41564681View in MoNA
Toxicity Profile
Route of ExposureNot Available
Mechanism of ToxicityGHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate, the principal excitatory neurotransmitter. Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,[19] low concentrations stimulate dopamine release via the GHB receptor.[20] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut.[21] After an initial phase of inhibition, dopamine release is then increased via the GHB receptor. This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness.
Metabolism Route of Elimination: Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. Fecal and renal excretion is negligible. 5% renal elimination. Half Life: 30 to 60 minutes
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesUsed as a general anesthetic, to treat conditions such as insomnia, clinical depression, narcolepsy, and alcoholism, and to improve athletic performance.
Minimum Risk LevelNot Available
Health EffectsChronically high levels of 4-hydroxybutyric acid are associated with the inborn errors of metabolism called: 4-Hydroxybutyric Aciduria/Succinic Semialdehyde Dehydrogenase Deficiency.
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01440
HMDB IDHMDB00710
PubChem Compound ID3037032
ChEMBL IDCHEMBL1342
ChemSpider ID2300886
KEGG IDC00989
UniProt IDNot Available
OMIM ID
ChEBI ID16724
BioCyc IDCPD-3193
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkGamma-Hydroxybutyric_acid
References
Synthesis Reference

Joseph Klosa, “Production of nonhygroscopic salts of 4-hydroxybutyric acid.” U.S. Patent US4393236, issued March, 1963.

MSDST3D4269.pdf
General References
  1. LeBeau MA, Montgomery MA, Morris-Kukoski C, Schaff JE, Deakin A, Levine B: A comprehensive study on the variations in urinary concentrations of endogenous gamma-hydroxybutyrate (GHB). J Anal Toxicol. 2006 Mar;30(2):98-105. [16620539 ]
  2. Kankaanpaa A, Liukkonen R, Ariniemi K: Determination of gamma-hydroxybutyrate (GHB) and its precursors in blood and urine samples: a salting-out approach. Forensic Sci Int. 2007 Aug 6;170(2-3):133-8. Epub 2007 Jul 20. [17658710 ]
  3. Gibson KM, Baumann C, Ogier H, Rossier E, Vollmer B, Jakobs C: Pre- and postnatal diagnosis of succinic semialdehyde dehydrogenase deficiency using enzyme and metabolite assays. J Inherit Metab Dis. 1994;17(6):732-7. [7707697 ]
  4. Gibson KM, Aramaki S, Sweetman L, Nyhan WL, DeVivo DC, Hodson AK, Jakobs C: Stable isotope dilution analysis of 4-hydroxybutyric acid: an accurate method for quantification in physiological fluids and the prenatal diagnosis of 4-hydroxybutyric aciduria. Biomed Environ Mass Spectrom. 1990 Feb;19(2):89-93. [2407302 ]
  5. Shinka T, Inoue Y, Ohse M, Ito A, Ohfu M, Hirose S, Kuhara T: Rapid and sensitive detection of urinary 4-hydroxybutyric acid and its related compounds by gas chromatography-mass spectrometry in a patient with succinic semialdehyde dehydrogenase deficiency. J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Aug 25;776(1):57-63. [12127325 ]
  6. Ergezinger K, Jeschke R, Frauendienst-Egger G, Korall H, Gibson KM, Schuster VH: Monitoring of 4-hydroxybutyric acid levels in body fluids during vigabatrin treatment in succinic semialdehyde dehydrogenase deficiency. Ann Neurol. 2003 Nov;54(5):686-9. [14595661 ]
  7. Brown GK, Cromby CH, Manning NJ, Pollitt RJ: Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: evidence of alpha-oxidation of 4-hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial beta-oxidation. J Inherit Metab Dis. 1987;10(4):367-75. [3126356 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Virus receptor activity
Specific Function:
Riboflavin transporter. Riboflavin transport is Na(+)-independent but moderately pH-sensitive. Activity is strongly inhibited by riboflavin analogs, such as lumiflavin. Weakly inhibited by flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). In case of infection by retroviruses, acts as a cell receptor to retroviral envelopes similar to the porcine endogenous retrovirus (PERV-A).
Gene Name:
SLC52A2
Uniprot ID:
Q9HAB3
Molecular Weight:
45776.61 Da
References
  1. Castelli MP, Mocci I, Pistis M, Peis M, Berta D, Gelain A, Gessa GL, Cignarella G: Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate receptor in the rat brain. Eur J Pharmacol. 2002 Jun 20;446(1-3):1-5. [12098579 ]
  2. Castelli MP, Ferraro L, Mocci I, Carta F, Carai MA, Antonelli T, Tanganelli S, Cignarella G, Gessa GL: Selective gamma-hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of gamma-hydroxybutyric acid. J Neurochem. 2003 Nov;87(3):722-32. [14535954 ]
General Function:
Ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity).
Gene Name:
GABRB1
Uniprot ID:
P18505
Molecular Weight:
54234.085 Da
References
  1. Maitre M, Humbert JP, Kemmel V, Aunis D, Andriamampandry C: [A mechanism for gamma-hydroxybutyrate (GHB) as a drug and a substance of abuse]. Med Sci (Paris). 2005 Mar;21(3):284-9. [15745703 ]