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1 Melanin Chemistry
Specifically, 4-tert-butylphenol (4-TBP), monobenzone, 4-S-cysteaminylphenol
(4-S-CAP), and rhododendrol (RD) are oxidized in the presence of mushroom tyrosinase [105–108]. Human tyrosinase-catalyzed oxidation of 4-TBP and RD was also
reported [105, 109]. Thus, the formed o-quinones are usually highly reactive toward
nucleophiles (chemical species that form a coordinate bond by donating an electron
pair), and thereby the inherent chemical instability may influence on cytotoxicity.
The above phenols, at a certain level of high concentration, cause melanocytespecific cytotoxicity as well as melanogenesis inhibition. Due to such cytotoxic
effects, these phenols can be a double-edged sword to the use in dermatology and
cosmetics; they may cause leukoderma as observed in pigmentary disorders as well
as skin-whitening.
Cytotoxic effects of these phenolic compounds and its applications in dermatology
have been widely investigated. 4-TBP and monobenzone are well-known compounds
because of their depigmentation effects. Especially, monobenzone is now clinically
used for depigmentation therapy, in which the patchy depigmented lesions of vitiligo
patients are treated with monobenzone to make them uniformly white [110].
An in vitro study using melanocytes showed that 4-TBP and monobenzone activated oxidative response and unfolded protein response (UPR), and thus upregulated
expression of pro-inflammatory cytokines [111]. These results indicate that 4-TBP
and monobenzone may activate an autoimmune response through endoplasmic reticulum stress due to ROS generation. As a cytotoxic effect, 4-TBP induces apoptosis (a
form of programmed cell death mainly through caspase activation pathways) [112],
while monobenzone induces necrosis (an unregulated form of cell death/damage that
does not follow apoptosis-associated signaling pathways) [110]. Another experiment
using melanoma showed several immunogenic effects upon monobenzone treatment
[113]. In the treated cells, melanosomes were subjected to autophagy (a mechanism
by which cellular materials are degraded through membrane trafficking processes),
tyrosinase was ubiquitinated (binding of ubiquitin to be degraded by proteases), and
exosomes (membrane-bound extracellular vesicles) that contains melanoma antigen
recognized by T-cell 1 (MART-1) and tyrosinase were released. A co-culture experiment of melanoma with dendritic cells showed activation of dendritic cells, and
further addition of blood cells induced cytotoxic melanoma-reactive T-cells. These
results suggest possible mechanisms of monobenzone-induced immunogenicity;
monobenzone binds tyrosinase or other proteins to be an antigen, which is partly
secreted outside and then (through cross-presentation by the activated dendritic cells)
cytotoxic T-cells emerge.
4-S-CAP and its derivatives have been investigated as candidates of antimelanoma drugs. An in vitro experiment showed that N-propionyl-4-S-CAP caused
apoptotic cell death of melanoma and increased ROS production [114]. Furthermore,
in a mouse melanoma model experiment, intratumoral injection of N-propionyl4-S-CAP suppressed tumor growth and mediated cytotoxic TRP2-specific T-cells
[114].
RD had been used in cosmetics as a skin-whitening agent in Japan until 2013, when
it was recalled because of cytotoxic adverse effects causing vitiligo-like leukoderma.
From an in vitro experiment, the viability of RD-treated melanocytes decreased in a
1 Melanin Chemistry
Specifically, 4-tert-butylphenol (4-TBP), monobenzone, 4-S-cysteaminylphenol
(4-S-CAP), and rhododendrol (RD) are oxidized in the presence of mushroom tyrosinase [105–108]. Human tyrosinase-catalyzed oxidation of 4-TBP and RD was also
reported [105, 109]. Thus, the formed o-quinones are usually highly reactive toward
nucleophiles (chemical species that form a coordinate bond by donating an electron
pair), and thereby the inherent chemical instability may influence on cytotoxicity.
The above phenols, at a certain level of high concentration, cause melanocytespecific cytotoxicity as well as melanogenesis inhibition. Due to such cytotoxic
effects, these phenols can be a double-edged sword to the use in dermatology and
cosmetics; they may cause leukoderma as observed in pigmentary disorders as well
as skin-whitening.
Cytotoxic effects of these phenolic compounds and its applications in dermatology
have been widely investigated. 4-TBP and monobenzone are well-known compounds
because of their depigmentation effects. Especially, monobenzone is now clinically
used for depigmentation therapy, in which the patchy depigmented lesions of vitiligo
patients are treated with monobenzone to make them uniformly white [110].
An in vitro study using melanocytes showed that 4-TBP and monobenzone activated oxidative response and unfolded protein response (UPR), and thus upregulated
expression of pro-inflammatory cytokines [111]. These results indicate that 4-TBP
and monobenzone may activate an autoimmune response through endoplasmic reticulum stress due to ROS generation. As a cytotoxic effect, 4-TBP induces apoptosis (a
form of programmed cell death mainly through caspase activation pathways) [112],
while monobenzone induces necrosis (an unregulated form of cell death/damage that
does not follow apoptosis-associated signaling pathways) [110]. Another experiment
using melanoma showed several immunogenic effects upon monobenzone treatment
[113]. In the treated cells, melanosomes were subjected to autophagy (a mechanism
by which cellular materials are degraded through membrane trafficking processes),
tyrosinase was ubiquitinated (binding of ubiquitin to be degraded by proteases), and
exosomes (membrane-bound extracellular vesicles) that contains melanoma antigen
recognized by T-cell 1 (MART-1) and tyrosinase were released. A co-culture experiment of melanoma with dendritic cells showed activation of dendritic cells, and
further addition of blood cells induced cytotoxic melanoma-reactive T-cells. These
results suggest possible mechanisms of monobenzone-induced immunogenicity;
monobenzone binds tyrosinase or other proteins to be an antigen, which is partly
secreted outside and then (through cross-presentation by the activated dendritic cells)
cytotoxic T-cells emerge.
4-S-CAP and its derivatives have been investigated as candidates of antimelanoma drugs. An in vitro experiment showed that N-propionyl-4-S-CAP caused
apoptotic cell death of melanoma and increased ROS production [114]. Furthermore,
in a mouse melanoma model experiment, intratumoral injection of N-propionyl4-S-CAP suppressed tumor growth and mediated cytotoxic TRP2-specific T-cells
[114].
RD had been used in cosmetics as a skin-whitening agent in Japan until 2013, when
it was recalled because of cytotoxic adverse effects causing vitiligo-like leukoderma.
From an in vitro experiment, the viability of RD-treated melanocytes decreased in a