6 research outputs found
Bioactivation of Cinnamic Alcohol Forms Several Strong Skin Sensitizers
Cinnamic
alcohol is a frequent contact allergen, causing allergic
contact dermatitis (ACD) in a substantial number of individuals sensitized
from contacts with fragrances. Hence, cinnamic alcohol is one of the
constituents in fragrance mix I (FM I) used for screening contact
allergy in dermatitis patients. Cinnamic alcohol lacks structural
alerts for protein reactivity and must therefore be activated by either
air oxidation or bioactivation to be able to act as a sensitizer.
In the present study, we explored the bioactivation of cinnamic alcohol
using human liver microsomes (HLM), and the potential pathways for
these reactions were modeled by <i>in silico</i> (DFT) techniques.
Subsequently, the reactivity of cinnamic alcohol and its metabolites
toward a model hexapeptide were investigated. In addition to cinnamic
aldehyde and cinnamic acid, two highly sensitizing epoxides previously
unobserved in studies of bioactivation were detected in the incubations
with HLMs. Formation of epoxy cinnamic aldehyde was shown (both by
the liver microsomal experiments, in which no depletion of epoxy cinnamic
alcohol was observed after initial formation, and by the very high
activation energy found for the oxidation thereof by calculations)
to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol
Skin Sensitization of Epoxyaldehydes: Importance of Conjugation
Structure–activity
relationship (SAR) models are important
tools for predicting the skin sensitization potential of new compounds
without animal testing. In compounds possessing a structural alert
(aldehyde) and an activation alert (double bond), it is important
to consider bioactivation/autoxidation (e.g., epoxidation). In the
present study, we have explored a series of aldehydes with regard
to contact allergy. The chemical reactivity of these 6 aldehydes toward
a model hexapeptide was investigated, and their skin sensitization
potencies were evaluated using the local lymph node assay (LLNA).
Overall, we observed a similar trend for the <i>in vitro</i> reactivity and the <i>in vivo</i> sensitization potency
for the structural analogues in this study. The highly reactive conjugated
aldehydes (α,β-unsaturated aldehydes and 2,3-epoxyaldehydes)
are sensitizing moieties, while nonconjugated aldehydes and nonterminal
aliphatic epoxides show low reactivity and low sensitization potency.
Our data show the importance of not only double bond conjugation to
aldehyde but also epoxide–aldehyde conjugation. The observations
indicate that the formation of nonconjugated epoxides by bioactivation
or autoxidation is not sufficient to significantly increase the sensitization
potency of weakly sensitizing parent compounds
Analogues of the Epoxy Resin Monomer Diglycidyl Ether of Bisphenol F: Effects on Contact Allergenic Potency and Cytotoxicity
Diglycidyl ethers of bisphenol A (DGEBA) and bisphenol
F (DGEBF)
are widely used as components in epoxy resin thermosetting products.
They are known to cause occupational and nonoccupational allergic
contact dermatitis. The aim of this study is to investigate analogues
of DGEBF with regard to contact allergy and cytotoxicity. A comprehensive
knowledge of the structural features that contribute to the allergenic
and cytotoxic effects of DGEBF will guide the development of future
novel epoxy resin systems with reduced health hazards for those coming
into contact with them. It was found that the allergenic effects of
DGEBF were dependent on its terminal epoxide groups. In contrast,
it was found that the cytotoxicity in monolayer cell culture was dependent
not only on the presence of epoxide groups but also on other structural
features
Epoxy Resin Monomers with Reduced Skin Sensitizing Potency
Epoxy
resin monomers (ERMs), especially diglycidyl ethers of bisphenol
A and F (DGEBA and DGEBF), are extensively used as building blocks
for thermosetting polymers. However, they are known to commonly cause
skin allergy. This research describes a number of alternative ERMs,
designed with the aim of reducing the skin sensitizing potency while
maintaining the ability to form thermosetting polymers. The compounds
were designed, synthesized, and assessed for sensitizing potency using
the in vivo murine local lymph node assay (LLNA). All six epoxy resin
monomers had decreased sensitizing potencies compared to those of
DGEBA and DGEBF. With respect to the LLNA EC<sub>3</sub> value, the
best of the alternative monomers had a value approximately 2.5 times
higher than those of DGEBA and DGEBF. The diepoxides were reacted
with triethylenetetramine, and the polymers formed were tested for
technical applicability using thermogravimetric analysis and differential
scanning calorimetry. Four out of the six alternative ERMs gave polymers
with a thermal stability comparable to that obtained with DGEBA and
DGEBF. The use of improved epoxy resin monomers with less skin sensitizing
effects is a direct way to tackle the problem of contact allergy to
epoxy resin systems, particularly in occupational settings, resulting
in a reduction in the incidence of allergic contact dermatitis
Epoxyalcohols: Bioactivation and Conjugation Required for Skin Sensitization
Allylic
alcohols, such as geraniol <b>1</b>, 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 <i>in vivo</i>, <i>in vitro</i>, <i>in chemico</i>, and <i>in silico</i> 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 <b>2</b>, where formation of the epoxide weakens the sensitization
potential
Epoxyalcohols: Bioactivation and Conjugation Required for Skin Sensitization
Allylic
alcohols, such as geraniol <b>1</b>, 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 <i>in vivo</i>, <i>in vitro</i>, <i>in chemico</i>, and <i>in silico</i> 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 <b>2</b>, where formation of the epoxide weakens the sensitization
potential