1.
Sources and Structure
1.1
Sources
Limonene has its name derived from 'Lemon', the food source that is most abundant in limonene and among the first sources discovered. It is found in:
1.2
Structure
Limonene is known as a monoterpene molecule (having one isoterpene in its structure) as well as a cyclic terpene (having a six-carboned ring structure).[6] Alongside Limonene, a well-researched compound is its metabolite 'Perillyl Aldcohol'.
2.
Limonene pharmacology
Limonene is colourless hydrocarbon compound that smells of oranges. Despite the scent, it is at highest levels in the rinds of lemons, where it acquires its name from.[1]
Limonene is rapidly and almost wholly absorbed in the GI tract after ingestion, and then gets divided to various body tissues after first pass metabolism in the liver[7] where it may be subject to metabolism into carveol metabolites or perillyl metabolites by CYP2C enzymes[8] of which inter-species differences exist.[9]
After a 1.6g dose, between 52-83% of the dose is excreted in 48 hours[10] and no build up of the compound is seen 21 days after cessation.[11] The half-life of D-limonene in humans is estimated to be between 12 and 24 hours.[11]
The primary metabolites of limonene in humans are perillic acid, dihydroperillic acid, and limonene-1,2-diol.[12] These metabolites are glucuronidated by the liver and excreted via the urine.
3.
Limonene from food sources
Serum limonene and metabolite levels are able to be elevated via food consumption. A 30-40 oz. serving of 'Mediterranean Style' lemonade (made with the whole lemons) contains 447-596mg limonene. [13] The termination half-life of perillic acid is shorter than that of D-limonene (in the range of 0.82-1.84 hours) and spiked serum levels of perillic acid 2.08 to 13.98 μM.
Standard Citrus juices in western nations (made without the rind) contain up to 100mg per litre of juice, whereas juices made with the rind included contain up to 1027mg per litre.[14][13]
4.
Limonene and liver health
In those with Non-alcoholic Fatty Liver disease (onset by diet), supplementation with D-limonene has been shown (in rats) to reverse the hepatic fatty acid buildup as well as downstream effects caused by the hepatic impairment.[15]</di|authors=Victor Antony Santiago J, Jayachitra J, Shenbagam M, Nalini N|journal=Eur J Nutr]
5.
Limonene and body fat
At this moment in time, no scientific consensus exists on D-limonene's role in adipocytes. Select anecdotes, however, suggest it may induce weight loss in high doses.
It, as well as the metabolite perillic acid, do build up in adipocytes over time[16][17], which ensures it can actually get to fat cells. Beyond that, it might exert fat-burning effects via suppression of insulin secretion in response to nutrients at pancreatic cells[18] or perhaps vicariously through possibly being an adenosine A(2A) agonistic ligand.[19]
6.
Limonene and Cancer
Dietary D-Limonene, as a monoterpene structure, is an anti-carcinogenic agent in various models of cancer including; skin, kidney, lung, forestomach, and mammary models.[20][21][22][13]
It seems to exert most carcinogenic effects by prevention of protein prenylation[23] at advanced stages of tumorogenesis, and by increasing levels of glutathione in the earlier stages as a preventative measure.[24] Some Phase 1 enzymes of the liver are also affected positively.[25]
7.
Safety
Limonene is a fairly safe compound to supplement, and has a Generally Recognized as Safe (GRAS) listing for being a food additive.[1]
It has no significant toxicity in humans. Past research indicated it may accelerate formation of tumors, however this result was found in rats and has since been shown to be of no significance to human metabolism.[26]
References
- ^Sun JD-Limonene: safety and clinical applicationsAltern Med Rev.(2007 Sep)
- ^Perez-Cacho PR, Rouseff RLFresh squeezed orange juice odor: a reviewCrit Rev Food Sci Nutr.(2008 Aug)
- ^Limem-Ben Amor I, Boubaker J, Ben Sgaier M, Skandrani I, Bhouri W, Neffati A, Kilani S, Bouhlel I, Ghedira K, Chekir-Ghedira LPhytochemistry and biological activities of Phlomis speciesJ Ethnopharmacol.(2009 Sep 7)
- ^Acharya A, Das I, Singh S, Saha TChemopreventive properties of indole-3-carbinol, diindolylmethane and other constituents of cardamom against carcinogenesisRecent Pat Food Nutr Agric.(2010 Jun)
- ^Satomi Y, Ohara K, Yazaki K, Ito M, Honda G, Nishino HProduction of the monoterpene limonene and modulation of apoptosis-related proteins in embryonic-mouse NIH 3T3 fibroblast cells by introduction of the limonene synthase gene isolated from Japanese catnip (Schizonepeta tenuifolia)Biotechnol Appl Biochem.(2009 Mar)
- ^Hyatt DC, Youn B, Zhao Y, Santhamma B, Coates RM, Croteau RB, Kang CStructure of limonene synthase, a simple model for terpenoid cyclase catalysisProc Natl Acad Sci U S A.(2007 Mar 27)
- ^Crowell PL, Elson CE, Bailey HH, Elegbede A, Haag JD, Gould MNHuman metabolism of the experimental cancer therapeutic agent d-limoneneCancer Chemother Pharmacol.(1994)
- ^Miyazawa M, Shindo M, Shimada TMetabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomesDrug Metab Dispos.(2002 May)
- ^Shimada T, Shindo M, Miyazawa MSpecies differences in the metabolism of (+)- and (-)-limonenes and their metabolites, carveols and carvones, by cytochrome P450 enzymes in liver microsomes of mice, rats, guinea pigs, rabbits, dogs, monkeys, and humansDrug Metab Pharmacokinet.(2002)
- ^Kodama R, Yano T, Furukawa K, Noda K, Ide HStudies on the metabolism of d-limonene (p-mentha-1,8-diene). IV. Isolation and characterization of new metabolites and species differences in metabolismXenobiotica.(1976 Jun)
- ^Vigushin DM, Poon GK, Boddy A, English J, Halbert GW, Pagonis C, Jarman M, Coombes RCPhase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials CommitteeCancer Chemother Pharmacol.(1998)
- ^Crowell PL, Lin S, Vedejs E, Gould MNIdentification of metabolites of the antitumor agent d-limonene capable of inhibiting protein isoprenylation and cell growthCancer Chemother Pharmacol.(1992)
- ^Pharmacokinetics of Perillic Acid in Humans after a Single Dose Administration of a Citrus Preparation Rich in d-Limonene Content
- ^Assessing Dietary D-Limonene Intake for Epidemiological Studies
- ^Dietary d-limonene alleviates insulin resistance and oxidative stress-induced liver injury in high-fat diet and L-NAME-treated rats(2011 Mar 29. [Epub ahead of print)
- ^Miller JA, Hakim IA, Chew W, Thompson P, Thomson CA, Chow HHAdipose tissue accumulation of d-limonene with the consumption of a lemonade preparation rich in d-limonene contentNutr Cancer.(2010)
- ^Miller JA, Hakim IA, Thomson C, Thompson P, Chow HHDetermination of d-limonene in adipose tissue by gas chromatography-mass spectrometryJ Chromatogr B Analyt Technol Biomed Life Sci.(2008 Jul 1)
- ^Metz SA, Rabaglia ME, Stock JB, Kowluru AModulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteinsBiochem J.(1993 Oct 1)
- ^Park HM, Lee JH, Yaoyao J, Jun HJ, Lee SJLimonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptorsBiochem Biophys Res Commun.(2011 Jan 7)
- ^Crowell PLMonoterpenes in breast cancer chemopreventionBreast Cancer Res Treat.(1997 Nov-Dec)
- ^Crowell PLPrevention and therapy of cancer by dietary monoterpenesJ Nutr.(1999 Mar)
- ^Tsuda H, Ohshima Y, Nomoto H, Fujita K, Matsuda E, Iigo M, Takasuka N, Moore MACancer prevention by natural compoundsDrug Metab Pharmacokinet.(2004 Aug)
- ^Gelb MH, Tamanoi F, Yokoyama K, Ghomashchi F, Esson K, Gould MNThe inhibition of protein prenyltransferases by oxygenated metabolites of limonene and perillyl alcoholCancer Lett.(1995 May 8)
- ^Effects of anticarcinogenic monoterpenes on phase II hepatic metabolizing enzymes
- ^Effects of monoterpenoids on in vivo DMBA-DNA adduct formation and on phase I hepatic metabolizing enzymes
- ^Flamm WG, Lehman-McKeeman LDThe human relevance of the renal tumor-inducing potential of d-limonene in male rats: implications for risk assessmentRegul Toxicol Pharmacol.(1991 Feb)