Methyl Chavicol
methyl_chavicol.png

Methyl chavicol is an
allylbenzene essential oil found primarily in the essential oil of sweet basil CT methyl chavicol.


Effects on P450 Enzymes

A 5-fold increase in CYP2B-associated PROD activity in both
male and female rats has been reported. Small increases in CYP1A2 activity were observed in female rats.[9]

A human liver in vitro test showed methyl chavicol inhibited CYP3A4 (IC50=5.9umol/l) and CYP1A (IC50=20 umol/l). There was no effect on CYP2D6.[8]


Metabolites of Methyl Chavicol in Human Urine

In a study by Sangster (1987), methyl chavicol (100 μg; 0.675 μmol) administered orally to humans was eliminated primarily in the urine and as CO2 in expired air. 65% of the total dose was recovered in urine and examined. No amount of methyl chavicol could be detected in urine. Methyl chavicol was completely metabolized by oxidative O-demethylation, and various oxidations of the side chain. In urine, six metabolites were identified:[11]

Chavicol (p-allylphenol) (47%)1 4-methyoxybenzoyl-N-glycine (12%)2
chavicol.png 4-methyoxybenzoyl-N-glycine.png
4-methoxyphenyllactic acid (4%) 4-methoxycinnamoylglycine (0.8%)
4-methoxyphenyllactic_acid.png 4-methoxycinnamoylglycine.png
4-methoxyphenylacetic acid (0.5%) 1'-hydroxyestragole (0.3%)
4-methoxyphenylacetic_acid.png 1-hydroxyestragole.png

Another test by Zeller, Horst, and Rychlik, found the following metabolites in human urine after the ingestion of fennel tea containing methyl chavicol:[12]

Chavicol (p-allylphenol) (17%) 1'-Hydroxyestragole (0.41%)
chavicol.png 1-hydroxyestragole.png

Methyl chavicol appeared to be completely metabolized. No methyl chavicol was detected in human urine.[12]

Metabolites of Methyl Chavicol in Vitro

Chavicol

chavicol.png
Chavicol is the O-demethyl metabolite of methyl chavicol.[10] This compound is itself an allylbenzene and can undergo bioactivation possibly leading to the formation of alkaloids in vivo as has been proven for similar allylbenzenes. The alkaloid forms of this allylbenzene are predicted to have stimulant action and no psychedelic action in man. P450 enzymes capable of O-demethylating allylbenzenes are typically CYP2D6 and CYP3A4 (CYP3A4 usually works in conjunction with CYP1A2 to carry out O-demethylation). CYP2C9 has also been shown to O-demethylate some compounds, and could potentially be involved in this reaction.

1'-Hydroxyestragole

1-hydroxyestragole.png
1'-Hydroxyestragole is created from methyl chavicol in human liver in vitro primarily by the P450 enzymes CYP1A2, CYP2A6 and CYP2E1 by 1-hydroxylation of methyl chavicol.[9][4]

This metabolite can form 1'-oxoestragole by the action of Estradiol 17beta-dehydrogenase Type 2 (17beta-HSD2).[4]

This metabolite also undergoes glucuronidation primarily by the action of UGT2B7 followed by UGT1A9, with a very small amount carried out by UGT2B15.[13] It undergoes sulfation by the action of SULT1A1 and SULT1A3.[14] These pathways prevent 1'-oxoestragole from forming.

1'-Oxoestragole

1-Oxoestragole.png
1'-Oxoestragole is created from 1'-hydroxyestragole by the action of estradiol-17beta-dehydrogenase Type 2 (17beta-HSD2).[4] This metabolite is then capable of forming adducts with glutathione (GSH) leading to inactivation, or forming adducts with endogenous amines.[4] The latter action is believed to be responsible for the psychedelic effects methyl chavicol is capable of producing in humans under certain conditions. For more details see the article: 1'-Oxoestragole.

Alkaloid Metabolites

Most allylbenzenes are capable of producing dimethylamine, piperidine, and pyrrolidine metabolites in vivo. This has been proven for safrole, elemicin, and several other allylbenzenes (see their individual articles for references). For this reason its highly probable that methyl chavicol also produces the same corresponding alkaloid metabolites.

The methyl chavicol metabolite 1'-Oxoestragole is capable of forming adducts with endogenous amines.[4] This action is believed to be responsible for the psychedelic effects methyl chavicol is capable of producing in humans under certain conditions.

The alkaloids in this section are all adducts of 1'-oxoestragole and endogenous amines.

Dimethylamine Adduct

3-%28dimethylamino%29-1-%284-methoxyphenyl%29propan-1-one.png

3-(dimethylamino)-1-(4-methoxyphenyl)propan-1-one is an adduct of 1'-oxoestragole and dimethylamine.

Piperidine Adduct

1-%284-methoxyphenyl%29-3-%28piperidin-1-yl%29propan-1-one.png

1-(4-methoxyphenyl)-3-(piperidin-1-yl)propan-1-one is an adduct of 1'-oxoestragole and piperidine.

Pyrrolidine Adduct

1-%284-methoxyphenyl%29-3-pyrrolidin-1-ylpropan-1-one.png

1-(4-methoxyphenyl)-3-pyrrolidin-1-ylpropan-1-one is an adduct of 1'-oxoestragole and pyrrolidine.


Psychedelic Activity

Alkaloid metabolites of methyl chavicol are presumed to be responsible for the psychedelic effects it produces under certain conditions in some human test subjects.

Methyl chavicol is active both orally and transdermally. Transdermal use is approximately 5-10 times more effective than oral use.

A single exposure to methyl chavicol without using oilahuasca activation techniques normally produces only very mild cannabis-like sedative effects without any psychedelic effects. Psychedelic effects are normally only achieved when used with various oilahuasca activators or on repeated use. Methyl chavicol appears to produce reverse tolerance. Anecdotal reports show that methyl chavicol's psychedelic effects are more pronounced when its used several times in a row in combination with several Oilahuasca Activation techniques.

Unlike many of the other allylbenzenes, methyl chavicol can be used as its own oilahuasca activator in some people. It also helps to activate other allylbenzenes. The exact reason for this is currently unknown. For details on how to help coerce psychedelic effects from methyl chavicol see the article on Oilahuasca Activation.


Natural Sources

Plant Origin Part Contents of Essential Oil
Sweet Basil Thailand Plant 93% [7]

Toxicity

Oral LD50 in rats: 1230 mg/kg [5]
Oral LD50 in mice: 1250 mg/kg [5]
Intraperitoneal LD50 in rats: 1030 mg/kg [6]
Intraperitoneal LD50 in mice: 1260 mg/kg [6]
Topical LD50 in rabbits: >5 gm/kg [5]


Chemical Properties

Synonyms: Estragole; 4-Methoxyallylbenzene
PubChem Compound ID: 8815
Molecular Weight: 148.20168 [g/mol]
Molecular Formula: C10H12O
Appearance: colorless liquid[3]
Boiling Point: 216 C @ 764 mm Hg[2]
Solubility: SOL IN ALCOHOL, CHLOROFORM[2]; Solubility in water at 25 deg C is 0.178 g/L.[1]
XLogP3: 3.4
IUPAC Name: 1-methoxy-4-prop-2-enylbenzene
InChI: InChI=1S/C10H12O/c1-3-4-9-5-7-10(11-2)8-6-9/h3,5-8H,1,4H2,2H3
InChIKey: ZFMSMUAANRJZFM-UHFFFAOYSA-N
Canonical SMILES: COC1=CC=C(C=C1)CC=C


Bibliography
1. Yalkoswky SH, Dannenfelser RM; Arizona Database of Aqueous Solubilites. Univ. of AZ, College of Pharmacy (1992)
2. Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 584
3. Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975., p. 156
4. 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
5. FCTXAV Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81.
6. COREAF Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965.
7. 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.
8. Safety evaluation of certain contaminants in food;
WHO FOOD ADDITIVES SERIES: 63, FAO JECFA, MONOGRAPHS 8; World Health Organization, Geneva, 2011; Food and Agriculture Organization of the United Nations, Rome, 2011; ISBN 978 92 4 166063 1 (WHO); ISBN 978-92-5-106736-9 (FAO); ISSN 0300-0923; Download Attached PDF Document
9. 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 Download Attached PDF Document
10. Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1'-hydroxyestragole.
Anthony A, Caldwell J, Hutt AJ, Smith RL. PubMed: 3121480
11. The metabolic disposition of [methoxy-14C]-labelled trans-anethole, estragole and p-propylanisole in human volunteers.
Sangster SA, Caldwell J, Hutt AJ, Anthony A, Smith RL. PubMed: 3424869
12. Study of the metabolism of estragole in humans consuming fennel tea.
Zeller A, Horst K, Rychlik M. PubMed: 19908891
13. Glucuronidation of 1'-hydroxyestragole (1'-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9.
Iyer LV, Ho MN, Shinn WM, Bradford WW, Tanga MJ, Nath SS, Green CE. PubMed: 12657745
14. Immunochemical identification of hepatic protein adducts derived from estragole.
Wakazono H, Gardner I, Eliasson E, Coughtrie MW, Kenna JG, Caldwell J. PubMed: 9705747
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License