Methyl Eugenol
methyl-eugenol.gif

Methyl Eugenol is an allylbenzene essential oil. It's similar to elemicin but missing one methoxy group on the benzene ring.


Commercial Use

It's used as a fruit fly attractant in agriculture, a flavouring agent
in jellies, baked goods, non-alcoholic beverages, chewing gum, candy, puddings, relishes and ice cream. It is also widely used as a fragrance ingredient in perfumes, toiletries and detergents. Methyl eugenol has been used as an anaesthetic
in rodents. [4]


Anecdotal Data On Psychedelic Activity

According to the current Oilahuasca Theory, the main active metabolite is presumed to be the piperidine alkaloid metabolite 1-(3,4-Dimethoxy-phenyl)-3-piperidin-1-yl-propan-1-one. The dimethylamine form of methyl eugenol is probably inactive. These conclusions are based on a single individual's Oilahuasca tests where supplementing with dimethylamine sources caused no effects, while supplementing with piperidine sources produced psychedelic effects in multiple tests. Until more tests are performed proving this is the case, this information should be treated as purely anecdotal.


Effects on P450 Enzymes in Rats

In vivo tests show CYP2B (PROD) and CYP1A2 (A4H) were induced by methyl eugenol in rat livers. Methyl eugenol induced an approximate 5-fold increase in CYP2B-associated PROD activity in both male and female rats. [3]

In another test, rats fed methyl eugenol at up to 50 mg/kg for 28 days showed no alteration in CYP1A2 or CYP2E1 expression levels (Ellis, 2007).


Pharmacokinetics in Man

Peak Serum Concentration

In Humans peak serum concentration of methyl eugenol occurs approximately 15 minutes after consumption. [4]

Half Life

In humans the half life for methyl eugenol is approximately 90 minutes. [4]

Skin Permeation

A study showed that methyl eugenol had a 14.5% permeation rate 30 minutes after a cosmetic cream containing 50 ppm of the compound was applied to the skin of a human volunteer. [4]


Metabolism in Man

Cytochrome P450 Enzymes

Human liver in vitro tests show that methyl eugenol is primarily metabolized by the cytochrome P450 enzymes CYP1A2 and CYP2C9. Enzymes playing a minor role are CYP2C19 and CYP2D6. [4]

Human liver in vitro tests show that methyl eugenol is not metabolized by CYP2A6. [4]

1′-hydroxymethyleugeol

In humans 1'-hydroxylation of methyl eugenol is primarily catalyzed by CYP1A2.[3] Some in vitro reports state that it is primarily catalyzed by both CYP1A2 and CYP2C9 and that CYP2C19 and CYP2D6 also play a minor role.[4]


Metabolism in Rats

In rats 1'-hydroxylation of methyl eugenol was shown to be catalyzed predominantly by CYP2E1 and probably CYP2C6 in one study. [3]


Metabolites In Human Liver In Vitro

The following data is based solely on in vitro tests.

It should be noted that in vivo tests will probably give drastically different results. Many in vitro tests of various allylbenzenes have detected large quantities of 1'-hydroxy metabolites and small quantities of 1'-oxo metabolites while in vivo tests usually show 1'-hydroxy metabolites as being only very minor metabolites, with 1'-oxo metabolites occurring in much larger quantities than 1'-hydroxy metabolites.

The reason for this discrepancy is usually because 1'-hydroxy metabolites are further metabolized in humans in vivo to give 1'-oxo metabolites. The enzyme producing 1'-oxo metabolites from 1'-hydroxy metabolites for the related allylbenzene methyl chavicol has been identified as Estradiol 17beta-dehydrogenase Type 2.[8] The human enzyme Estradiol 17beta-dehydrogenase Type 2 requires NAD+ as a cofactor, and unless NAD+ is available in the liver microsome tests, this enzyme won't function, and this can therefor radically skew in vitro test results.

In one in vitro test after incubation of methyl eugenol in liver microsomes of humans for 2 hours 8 metabolites were identified:

1'-Hydroxymethyleugenol 25%[7] 3'-Hydroxymethylisoeugenol 25%[7]
1-Hydroxymethyleugenol.png 3-Hydroxymethylisoeugenol.png
6-Hydroxymethyleugenol 1%[7] 1'-Oxomethyleugenol <1%[7]
6-Hydroxymethyleugenol.png 1-oxomethyleugenol.png
3'-Oxomethylisoeugenol 4%[7] Eugenol 4%[7]
3-Oxomethylisoeugenol.png Eugenol-UP.gif
Chavibetol 1%[7] Methyl eugenol glycol1 4%[7]
Chavibetol-UP.gif Methyl-Eugenol-Glycol.png

Natural Sources

Plant Origin Part Contents of Essential Oil
Anasarum canadense (Snakeroot) 36–45% [4]
Artemisia dracunculus (Russian tarragon) Russia 5–29% [4]
Cinnamomum cordatum Bark 92.1% [5]
Cinnamomum cordatum Leaf 4.4% [5]
Cinnamomum glanduliferum 45% [5]2
Cinnamomum culitlawan3 (Lawang oil) 41-50% [5]4
Cinnamomum cecidodaphne 45% [5]5
Cinnamomum oliveri Bail. leaves 90–95% [4]
Dacrydium franklinii (Huon pine) up to 98% [4]
Echinophora tenuifolia Turkey 17.5–50% [4]
Melaleuca bracteata (Black Tea Tree) up to 50% [4]
Melaleuca bracteata F.v.M. (Black Tea Tree) leaves 90–95% [4]
Melaleuca leucadendron (Cajeput Tree) up to 97% [4]
Ocimum basilicum var. ‘grand vert’ (basil) 55–65% [4]
Ocimum basilicum var. minimum (basil) 55–65% [4]
Ocimum sanctum L. (Holy Basil) plant 11.8% [2]
Ocotea pretiosa (Brazilian sassafras) Brazil up to 50% [4]
Pimenta dioica Jalisco, Mexico berries 62.7% [6]
Pimenta dioica Mexico berries 50-60%
Pimenta dioica Jamaica berries 10%
Pimenta racemosa var. racemosa (bay leaf) up to 48.1% [4]

Regulation

In the USA, methyl eugenol was affirmed as generally recognized as safe by the US Food and Drug Administration as a food additive under 21 CFR §172.515 (FDA, 2004). It is also permitted for direct addition to food for human consumption
as a synthetic flavouring substance in the USA (FDA, 2010). [4]


Chemical Properties

Synonyms: 3,4-dimethoxy-allylbenzene, 3,4-dimethoxyallylbenzene, 1,2-dimethoxy-4-prop-2-enylbenzene
PubChem CID:** 7127
Molecular Weight: 178.22766 [g/mol]
Molecular Formula: C11H14O2
Appearance: Colourless to pale yellow liquid[4]; Crystals from hexane[1]
Odor: clove-carnation odor[4]
Taste: bitter[4]
Boiling Point: 254.7 deg C[1]; bp30, 146–147 °C; bp760, 244 °C [4]
Melting Point: −2 °C [4]; -4 deg C[1]
Solubility: Soluble in ethanol, ethyl ether, chloroform and most other organic
solvents; insoluble in water, glycol and propylene glycol [4]
Volatility: Evaporates readily at room temperature [4]
Stability: Darkens and slowly thickens when exposed to air [4]
Octanol/water partition coefficient (P): log Kow, 3.45 [4]
XLogP3: 2.5
IUPAC Name: 1,2-dimethoxy-4-prop-2-enylbenzene
InChI: InChI=1S/C11H14O2/c1-4-5-9-6-7-10(12-2)11(8-9)13-3/h4,6-8H,1,5H2,2-3H3
InChIKey: ZYEMGPIYFIJGTP-UHFFFAOYSA-N
Canonical SMILES: COC1=C(C=C(C=C1)CC=C)OC


See Also


Bibliography
1. Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 867
2. Viyoch, J.; Pisutthanan, N.; Faikreua, A.; Nupangta, K.; Wangtorpol, K.; Ngokkuen, J.; Evaluation of in vitro antimicrobial activity of Thai basil oils and their micro-emulsion formulas against Propionibacterium acnes; International Journal of Cosmetic Science, 2006, vol. 28, issue 2, p 125, ISSN 01425463. ISBN 01425463.
3. Douglas W. Bristol, Ph.D., Study Scientist
NTP Technical Report on the 3-Month Toxicity Studies of Estragole; National Toxicology Program, Toxicity Report Series, Number 82; NIH Publication No. 11-5966; National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services
4. METHYLEUGENOL;
IARC MONOGRAPHS – 101 Download Attached PDF Document
5. Cinnamon and Cassia: The Genus Cinnamomum
K . Nirmal Babu , P . N . Ravindran , and M . Shylaja; CRC Press 2003; Print ISBN: 978-0-415-31755-9; eBook ISBN: 978-0-203-59087-4
6. Acaricidal effect and chemical composition of essential oils extracted from Cuminum cyminum, Pimenta dioica and Ocimum basilicum against the cattle tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae).
Martinez-Velazquez M, Castillo-Herrera GA, Rosario-Cruz R, Flores-Fernandez JM, Lopez-Ramirez J, Hernandez-Gutierrez R, Lugo-Cervantes Edel C. PubMed PMID: 20865426
7. Metabolism of methyleugenol in liver microsomes and primary hepatocytes: pattern of metabolites, cytotoxicity, and DNA-adduct formation.
Cartus AT, Herrmann K, Weishaupt LW, Merz KH, Engst W, Glatt H, Schrenk D. PubMed PMID: 22610610
8. Evaluation of human interindividual variation in bioactivation of estragole using physiologically based biokinetic modeling.
Punt A, Jeurissen SM, Boersma MG, Delatour T, Scholz G, Schilter B, van Bladeren PJ, Rietjens IM. PubMed: 19920071
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