Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer

Abstract

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho-quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4′-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol's haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn-7,4′-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn-7,4′-oxyneolignan. Computational studies reaffirmed the “syn” stereochemistry of the isolated 7,4′-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol’s strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Analysis and Stability Study of Isoeugenol in Aquaculture Products by Headspace Solid-Phase Microextraction Coupled to Gas Chromatography–Mass Spectrometry

“…It appears that isoeugenol (at least in part or temporarily) is converting to vanillin or one of its isomers; there may be other degradation products as well but that was not explored here. Previous researchers have observed isoeugenol degrading, for example in dried Piper betle extracts and as a pure standard but over a time frame of weeks. , Others have studied the conversion of isoeugenol to vanillin but have looked at the use of enzymes/catalysts for the reaction. − Here isoeugenol appears to be converting in pure LC-MS grade water. Figure a shows that isoeugenol’s concentration in water decreases as vanillin’s (or possibly an isomer which would share its exact mass transition ( m / z 151.0 → 136.01654)) concentration increases over 24 h; in this experiment, there was nothing else in the LC vial besides isoeugenol and LC-MS-grade water.…”

“…Previous researchers have observed isoeugenol degrading, for example in dried Piper betle extracts and as a pure standard but over a time frame of weeks. 26,27 Others have studied the conversion of isoeugenol to vanillin but have looked at the use of enzymes/catalysts for the reaction. 28−31 Here isoeugenol appears to be converting in pure LC-MS grade water.…”