Epoxyalcohols: Bioactivation and Conjugation Required for Skin Sensitization

Allylic
alcohols, such as geraniol 1, are easily oxidized
by varying mechanisms, including the formation of both 2,3-epoxides
and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can
be interconverted to each other, and the reactivity of them all must
be considered when considering the sensitization potential of the
parent allylic alcohol. An in-depth study of the possible metabolites
and autoxidation products of allylic alcohols is described, covering
the formation, interconversion, reactivity, and sensitizing potential
thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse
techniques to investigate the sensitization potential of a molecule,
allows the identification of potential candidate(s) for the true culprit(s)
in allergic responses to allylic alcohols. Overall, the sensitization
potential of the investigated epoxyalcohols and unsaturated alcohols
was found to derive from metabolic oxidation to the more potent aldehyde
where possible. Where this is less likely, the compound remains weakly
or nonsensitizing. Metabolic activation of a double bond to form a
nonconjugated, nonterminal epoxide moiety is not enough to turn a
nonsensitizing alcohol into a sensitizer, as such epoxides have low
reactivity and low sensitizing potency. In addition, even an allylic
2,3-epoxide moiety is not necessarily a potent sensitizer, as shown
for 2, where formation of the epoxide weakens the sensitization
potential.