Gamolenic acid

Identification

Name
Gamolenic acid
Accession Number
DB13854
Type
Small Molecule
Groups
Approved, Investigational
Description

Gamolenic acid, or gamma-linolenic acid (γ-Linolenic acid) or GLA, is an essential fatty acid (EFA) comprised of 18 carbon atoms with three double bonds [8] that is most commonly found in human milk and other botanical sources [1]. It is an omega-6 polyunsaturated fatty acid (PUFA) also referred to as 18:3n-6; 6,9,12-octadecatrienoic acid; and cis-6, cis-9, cis-12- octadecatrienoic acid [8]. Gamolenic acid is produced minimally in the body as the delta 6-desaturase metabolite of Alpha-Linolenic Acid. It is converted to Dihomo-gamma-linolenic acid, a biosynthetic precursor of monoenoic prostaglandins such as PGE1. While Gamolenic acid is found naturally in the fatty acid fractions of some plant seed oils [8], Evening primrose oil and Borage oil are rich sources of gamolenic acid. Evening primrose oil has been investigated for clinical use in menopausal syndrome, diabetic neuropathy, and breast pain, where gamolenic acid is present at concentrations of 7-14% [8]. Gamolenic acid may be found in over-the-counter dietary supplements. Gamolenic acid is also found in some fungal sources and also present naturally in the form of triglycerides [8]. Various clinical indications of gamolenic acid have been studied, including rheumatoid arthritis, atopic eczema, acute respiratory distress syndrome, asthma, premenstrual syndrome, cardiovascular disease, ulcerative colitis, ADHD, cancer, osteoporosis, diabetic neuropathy, and insomnia.

Structure
Thumb
Synonyms
  • (6,9,12)-linolenic acid
  • (6Z,9Z,12Z)-Octadecatrienoic acid
  • (Z,Z,Z)-6,9,12-octadecatrienoic acid
  • 18:3 (n-6)
  • 6-cis,9-cis,12-cis-octadecatrienoic acid
  • 6,9,12-Octadecatrienoic acid
  • all-cis-6,9,12-octadecatrienoic acid
  • gamma-Linolenic acid
  • gamoleic acid
  • GLA
  • Octadeca-6,9,12-triensäure
  • γ-linolenic acid
  • γ-Linolensäure
External IDs
NDI 609
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Beta-carotene 10000I.U. With Borage Oil CapGamolenic acid (90 mg) + Beta carotene (10000 unit)CapsuleOralJamieson Laboratories Ltd1993-12-311997-08-13Canada
Bio-efa Borage Gla 240 CapGamolenic acid (240 mg) + Linoleic acid (378 mg) + Vitamin E (10 unit)CapsuleOralPge Canada (86) Inc.1989-12-312006-06-19Canada
Bio-efa Borage Gla 90 CapGamolenic acid (90 mg) + Alpha-Linolenic Acid (1 mg) + Linoleic acid (216 mg) + Vitamin E (10 unit)CapsuleOralPge Canada (86) Inc.1989-12-312006-06-19Canada
Borage Oil CapsulesGamolenic acid (125 mg) + Borage oil (500 mg) + Linoleic acid (220 mg)CapsuleOralBioforce Canada Inc.1994-12-311999-10-14Canada
Borage Oil CapsulesGamolenic acid (258 mg) + Linoleic acid (375 mg) + Oleic Acid (148 mg) + Palmitic Acid (96 mg)CapsuleOralGeneral Nutrition Canada Inc.2001-10-152009-08-05Canada
Evening Primrose Oil Cap 500mg W Vit EGamolenic acid (40 mg) + Linoleic acid (350 mg) + Vitamin E (14.9 unit)CapsuleOralStanley Pharmaceuticals, A Division Of Vita Health Products Inc.1990-12-312002-07-31Canada
Gla 130 Primrose OilGamolenic acid (130 mg) + Linoleic acid (900 mg) + Oleic Acid (100 mg)CapsuleOralSeroyal International Inc.1996-01-312007-08-02Canada
Hi-GA Evening Primerose Oil LiqGamolenic acid (110 mg) + Linoleic acid (650 mg)LiquidOralHi Ga Health Inc.1991-12-311997-06-10Canada
Nuprimol CapGamolenic acid (45 mg) + D-alpha-Tocopherol acetate (13.6 unit) + Linoleic acid (340 mg) + Oleic Acid (45 mg)CapsuleOralNu Life Nutrition Ltd.1997-09-152005-03-15Canada
Pro-gla CapsGamolenic acid (90 mg) + Vitamin E (10 unit)CapsuleOralProfessional Health Products1989-12-312003-08-25Canada
Categories
UNII
78YC2MAX4O
CAS number
506-26-3
Weight
Average: 278.4296
Monoisotopic: 278.224580204
Chemical Formula
C18H30O2
InChI Key
VZCCETWTMQHEPK-QNEBEIHSSA-N
InChI
InChI=1S/C18H30O2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18(19)20/h6-7,9-10,12-13H,2-5,8,11,14-17H2,1H3,(H,19,20)/b7-6-,10-9-,13-12-
IUPAC Name
(6Z,9Z,12Z)-octadeca-6,9,12-trienoic acid
SMILES
CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O

Pharmacology

Indication

Indicated as a dietary supplement for over-the-counter uses.

Pharmacodynamics

Gamolenic acid is converted to PGE1, which exhibits anti-inflammatory, antithrombotic, antiproliferative, and lipid-lowering effects [8]. PGE1 also induces smooth muscle relaxation and vasodilation. Gamolenic acid is an essential component of membrane phospholipids, including the mitochondrial membrane, where it enhances the the integrity and the fluidity of the membrane [8].

Bone and joint health: In a pilot study of women with a mean age of 79.5 years and senile osteoporosis, the use of gamolenic acid in combination with calcium and eicosapentaenoic acid was associated with an increase in femoral bone density and lumbar spine density in comparison to placebo, where there were no observable changes [6]. In clinical studies of patients with rheumatoid arthritis, treatment with gamolenic acid-containing oils resulted in an improvement in symptoms, measured by joint tenderness counts and scores, joint swelling scores, physician global assessment, and pain [8].

Inflammation: A study demonstrated that oral administration of gamolenic acid suppressed human T-cell proliferation and activation by interfering with early events in the TcR/CD3-receptor–mediated signal transduction cascade [2].

Atherosclerosis: In ApoE genetic knock-out mice, dietary gamolenic acid was shown to reduce the average medial layer thickness of the vessel wall and reduces the size of atherosclerotic lesions [2].

Diabetic complications: In a clinical trial of patients with mild diabetic neuropathy or distal diabetic neuropathy, treatment with gamolenic acid was associated with improved symptoms in hot and cold threshold, sensation, tendon reflexes, and muscle strength [8]. GLA ameliorated the inflammatory profile in diabetic nephropathy in rat studies [3].

Cancer: In three human tumor cell lines (the neuroblastoma CHP-212, the tubal carcinoma TG, and the colon carcinoma SW-620), gamolenic acid elicited cytotoxic effects in tumours by blocking cell proliferation following incorporation into malignant cells [5]. In both clinical and animal studies of breast cancer, gamolenic acid, in combination with tamoxifen, down-regulated the expression of estrogen receptors [8].

Skin disorders: In an open study of patients with atopic dermatitis, which is a disorder related to a deficiency of delta-6-desaturase and inefficient conversion of linoleic acid to gamolenic acid, daily administration of gamolenic acid was associated with a significant increase in plasma GLA and DGLA levels in combination with an improvement of clinical signs of atopic dermatitis [7].

Respiratory disorders: In patients with acute lung injury or acute respiratory distress syndrome, gamolenic acid was shown to reduce cytokine production and neutrophil recruitment into the lung [1]. In patients with atopic asthma, gamolenic acid blocked ex vivo synthesis of leukotrienes from whole blood and isolated neutrophils compared to the placebo group [1].

Mechanism of action

Once gamolenic acid (GLA) is absorbed and converted to dihomo-gamolenic acid (DGLA), circulating DGLA fatty acids are converted to several lipid mediators with predominantly anti-inflammatory properties, such as prostaglandin-E1 (PGE1) and 15-HETrE. The anti-inflammatory effects of DGLA are attributed to both the anti-inflammatory properties of DGLA-derived metabolites and the ability of DGLA and its products to compete with arachidonic acid (AA) in the synthesis of pro-inflammatory potent eicosanoid products, such as prostaglandins, thromboxane and leukotrienes [1]. Both PGE1 and 15-HETrE are known to suppress inflammation, promote vasodilation, lower blood pressure, inhibit smooth muscle cell proliferation, inhibit platelet aggregation, and exert anti-neoplastic activities [1]. PGE1 is a potent vasodilator that binds to surface receptors on smooth muscle cells, increasing intracellular cAMP [8]. PGE1 is binds to G protein coupled surface PGE (EP) receptors and prostacyclin (IP) receptors as a natural ligand [2].

GLA is proposed to enhance calcium absorption, reduce excretion and increase calcium deposition in bone [6]. It is proposed that GLA may suppress tumor growth in vivo by increasing the expression of E-cadherin, a cell-to-cell adhesion molecule that acts as a suppressor of metastasis. Another possible mechanism of tumour suppression is that GLA also reduces tumor-endothelium adhesion, which is a key factor in the establishment of distant metastases, partly by improving gap junction communication within the endothelium [2]. By targeting the inflammatory process involved in the pathogenesis of diabetic nephropathy, GLA inhibits the expression of inflammatory mediators that tend be elevated in diabetes, intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), thereby attenuates the recruitment and infiltration of monocytes or macrophages [3].

Absorption

The findings from a pharmacokinetic study suggest that therapeutic levels of GLA can be achieved within a week. The fasting plasma GLA levels plateaued within seven days of beginning treatment, regardless of dose [8].

Volume of distribution

No pharmacokinetic data available.

Protein binding

No pharmacokinetic data available.

Metabolism

Via elongation mediated by elongase (ELOVL5), gamolenic acid is rapidly converted to dihomo-gamma-linolenic acid (DGLA), which is further cyclooxygenated to prostaglandin E1 (PGE1) via COX-1 or COX-2 enzymatic activity depending on the cell type [1]. PGE1 may be metabolized to smaller prostaglandin remnants, primarily dicarboxylic acids, which undergo renal excretion [8]. DGLA may be converted to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid (15-HETrE) by 15-lipoxygenase enzyme [1].

Although the enzymatic pathway is less predominant relative to ELOVL5 in most cells, DGLA may also be converted to arachidonic acid (AA) via delta-5-desaturate activity [4], where hydrogen atoms are selectively removed to create new double bonds F27]. Arachidonic acid is a precursor in the biosynthesis of prostaglandin E2, thromboxanes, and leukotrienes, which are potent inflammatory mediators and play an important role in inflammatory pathways.

Route of elimination

The metabolites of gamolenic acid is expected to undergo renal excretion [8].

Half life

No pharmacokinetic data available.

Clearance

No pharmacokinetic data available.

Toxicity

Oral TDLO reported in man is 3.14 mg/kg/42D (intermittent) [MSDS]. While limited cases of soft stool, belching, and abdominal bloating have been reported from dietary supplements containing gamolenic acid, daily doses up to 2.8 g were well tolerated [8].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe therapeutic efficacy of 7-Nitroindazole can be decreased when used in combination with Gamolenic acid.
AcetazolamideThe therapeutic efficacy of Acetazolamide can be decreased when used in combination with Gamolenic acid.
AmifampridineThe risk or severity of seizure can be increased when Gamolenic acid is combined with Amifampridine.
AmobarbitalThe therapeutic efficacy of Amobarbital can be decreased when used in combination with Gamolenic acid.
BarbexacloneThe therapeutic efficacy of Barbexaclone can be decreased when used in combination with Gamolenic acid.
BarbitalThe therapeutic efficacy of Barbital can be decreased when used in combination with Gamolenic acid.
BeclamideThe therapeutic efficacy of Beclamide can be decreased when used in combination with Gamolenic acid.
BrivaracetamThe therapeutic efficacy of Brivaracetam can be decreased when used in combination with Gamolenic acid.
ButalbitalThe therapeutic efficacy of Butalbital can be decreased when used in combination with Gamolenic acid.
CannabidivarinThe therapeutic efficacy of Cannabidivarin can be decreased when used in combination with Gamolenic acid.
Food Interactions
Not Available

References

General References
  1. Sergeant S, Rahbar E, Chilton FH: Gamma-linolenic acid, Dihommo-gamma linolenic, Eicosanoids and Inflammatory Processes. Eur J Pharmacol. 2016 Aug 15;785:77-86. doi: 10.1016/j.ejphar.2016.04.020. Epub 2016 Apr 12. [PubMed:27083549]
  2. Fan YY, Chapkin RS: Importance of dietary gamma-linolenic acid in human health and nutrition. J Nutr. 1998 Sep;128(9):1411-4. doi: 10.1093/jn/128.9.1411. [PubMed:9732298]
  3. Kim DH, Yoo TH, Lee SH, Kang HY, Nam BY, Kwak SJ, Kim JK, Park JT, Han SH, Kang SW: Gamma linolenic acid exerts anti-inflammatory and anti-fibrotic effects in diabetic nephropathy. Yonsei Med J. 2012 Nov 1;53(6):1165-75. doi: 10.3349/ymj.2012.53.6.1165. [PubMed:23074118]
  4. Chamberlin AJ, Bauer JE: Dietary gamma-linolenic acid supports arachidonic acid accretion and associated Delta-5 desaturase activity in feline uterine but not ovarian tissues. J Nutr Sci. 2014 Oct 13;3:e43. doi: 10.1017/jns.2014.41. eCollection 2014. [PubMed:26101612]
  5. Hrelia S, Bordoni A, Biagi P, Rossi CA, Bernardi L, Horrobin DF, Pession A: gamma-Linolenic acid supplementation can affect cancer cell proliferation via modification of fatty acid composition. Biochem Biophys Res Commun. 1996 Aug 14;225(2):441-7. doi: 10.1006/bbrc.1996.1192. [PubMed:8753781]
  6. Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH: Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998 Oct;10(5):385-94. [PubMed:9932142]
  7. Simon D, Eng PA, Borelli S, Kagi R, Zimmermann C, Zahner C, Drewe J, Hess L, Ferrari G, Lautenschlager S, Wuthrich B, Schmid-Grendelmeier P: Gamma-linolenic acid levels correlate with clinical efficacy of evening primrose oil in patients with atopic dermatitis. Adv Ther. 2014 Feb;31(2):180-8. doi: 10.1007/s12325-014-0093-0. Epub 2014 Jan 17. [PubMed:24435467]
  8. Gamma-Linolenic Acid (GLA) Monograph - Semantic Scholar [File]
External Links
Human Metabolome Database
HMDB0003073
KEGG Drug
D07213
KEGG Compound
C06426
ChemSpider
4444436
BindingDB
50269532
ChEBI
28661
ChEMBL
CHEMBL464982
Wikipedia
Gamma-Linolenic_acid
ATC Codes
D11AX02 — Gamolenic acidD11AX52 — Gamolenic acid, combinations
MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentFood Allergy1
3Unknown StatusTreatmentRheumatoid Arthritis1
Not AvailableCompletedTreatmentRheumatoid Arthritis, Juvenile1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral
LiquidOral
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000254 mg/mLALOGPS
logP6.59ALOGPS
logP6.06ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)4.92ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity89.64 m3·mol-1ChemAxon
Polarizability33.8 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-MS (1 TMS)GC-MSsplash10-005c-9800000000-7b6e7a36b048f5ed69bd
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-EI-TOFGC-MSsplash10-00b9-9300000000-254ecb989081fdc719d2
GC-MS Spectrum - GC-MSGC-MSsplash10-005c-9800000000-7b6e7a36b048f5ed69bd
Mass Spectrum (Electron Ionization)MSsplash10-00nf-9200000000-cf911df79059a750cb2a
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 20V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 30V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 10V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF , NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 20V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 30V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 10V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF 10V, NegativeLC-MS/MSNot Available
MS/MS Spectrum - ESI-TOF , NegativeLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QTOF , negativeLC-MS/MSsplash10-004i-0090000000-dcae4273443fd52bbb03
LC-MS/MS Spectrum - LC-ESI-TOF , negativeLC-MS/MSsplash10-004i-0090000000-143e6ddfa05656a4c4da
LC-MS/MS Spectrum - LC-ESI-TOF , negativeLC-MS/MSsplash10-004i-0090000000-0b9ba563ad074fe141e8
LC-MS/MS Spectrum - LC-ESI-TOF , negativeLC-MS/MSsplash10-004i-0090000000-63bf7d731625d5577978

Taxonomy

Description
This compound belongs to the class of organic compounds known as lineolic acids and derivatives. These are derivatives of lineolic acid. Lineolic acid is a polyunsaturated omega-6 18 carbon long fatty acid, with two CC double bonds at the 9- and 12-positions.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Lineolic acids and derivatives
Direct Parent
Lineolic acids and derivatives
Alternative Parents
Long-chain fatty acids / Unsaturated fatty acids / Straight chain fatty acids / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Octadecanoid / Long-chain fatty acid / Fatty acid / Unsaturated fatty acid / Straight chain fatty acid / Monocarboxylic acid or derivatives / Carboxylic acid / Carboxylic acid derivative / Organic oxygen compound / Organic oxide
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
omega-6 fatty acid, linolenic acid (CHEBI:28661) / Unsaturated fatty acids, Polyunsaturated fatty acids (C06426) / Unsaturated fatty acids (LMFA01030141)

Drug created on June 23, 2017 14:49 / Updated on November 02, 2018 07:47