posted on 2023-04-12, 12:44authored byJongmin Ahn, Cristina Avonto, Pankaj Pandey, Shabana I. Khan, Ikhlas A. Khan, David W. Roberts, Amar G. Chittiboyina
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.