Structure and identity
Caryophyllene is notable for having a cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature. Its IUPAC name is (1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene. (-)-Beta-caryophyllene is the most commonly occurring form of beta-caryophyllene, and it occurs in many essential oils, particularly oil of cloves. The molecular formula is C₁₅H₂₄ and the molecular weight is 204.35. In the (-) form, the stereocentre next to the exocyclic double bond has S configuration and the remaining stereocentre has R configuration; the (+) form is its enantiomer. Caryophyllene has roles as an insect attractant, a metabolite and a non-steroidal anti-inflammatory drug.
Occurrence
Caryophyllene is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves), and the essential oils of Cannabis sativa, copaiba, rosemary and hops. It is usually found as a mixture with isocaryophyllene, the cis double bond isomer, and α-humulene, a ring-opened isomer. Caryophyllene is a common sesquiterpene among plant species. Beta-caryophyllene is among the most abundant plant essential oil components. It has also been reported in Camellia sinensis and Trichogonia grazielae.
Cannabis flower essential oil contains approximately 3.8-37.5% caryophyllene, and clove bud essential oil approximately 1.7-19.5%. The essential oil of hops contains approximately 5.1-14.5% caryophyllene and that of oregano approximately 4.9-15.7%. In the essential oil of Piper nigrum, β-caryophyllene makes up 9.5%, and in white pepper oil 14.4%. Other oils give approximately 7.8% in black caraway, 4.62-7.55% in lavender, 6.9-11.1% in true cinnamon, 3.1-10.7% in ylang-ylang and 25.3% in malabathrum (Cinnamomum tamala).
White pepper is a processed product of Piper nigrum: the fruit is collected when reddish, the outer black skin is peeled off and the fruit is sun dried. The oils of black pepper and white pepper are both dominated by monoterpenes, with α-pinene, β-pinene, 3-carene, limonene and β-caryophyllene among their main components. Sesquiterpenes make up 12.3% of Piper nigrum oil and 19.6% of white pepper oil.
Biosynthesis
Caryophyllene is biosynthesized from the common terpene precursors dimethylallyl pyrophosphate and isopentenyl pyrophosphate. In the last step, farnesyl pyrophosphate undergoes an enzyme-catalyzed intramolecular cyclization to form caryophyllene.
Properties and safety
Caryophyllene is insoluble in water and soluble in oils and ether. It is also soluble in ethanol. Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects. Caryophyllene has an LD50 of 5,000 mg/kg in mice. Oxidized beta-caryophyllene is on the list of established contact allergens in humans.
The FDA has designated caryophyllene generally recognized as safe (GRAS) and approves it as a food additive, usually for flavoring. Its compendial status is the Food Chemicals Codex. It carries the GHS hazard statements H304 and H317. A safety data sheet describes it as a skin irritant and as harmful by ingestion, with a risk of lung damage by aspiration. In acute studies it caused local anesthesia in the eyes of rabbits and inflammation after oral dosing in mice.
Metabolism and biological activity
14-Hydroxycaryophyllene oxide (C₁₅H₂₄O₂) was isolated from the urine of rabbits treated with (-)-caryophyllene (C₁₅H₂₄). Beta-caryophyllene is under basic research for its potential action as an agonist of the cannabinoid receptor type 2 (CB2 receptor). Given orally at under 5 mg/kg, it produced strong anti-inflammatory and analgesic effects in wild-type mice but not in CB2 receptor knockout mice.
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