1.6 Melanin Chemistry in Relation to Melanocyte-Specific Cytotoxicity
23
dose-dependent manner, which could be associated with the observed UPR activation
and be caused by induced apoptotic pathways [115]. From a chemical experiment,
the formation of super oxide radicals was also shown when RD was oxidated with
tyrosinase [108].
1.6.2 o-Quinones and Melanocyte-Specific Cytotoxicity
The above introduced cytotoxicity, in part, is presumably associated with the reaction between intracellular thiols and o-quinones generated by phenol or catechol
oxidation. (However, note that there is also a report showing that the cytotoxicity
of 4-TBP is not correlated with tyrosinase activity [112].) As previously stated,
o-quinones are highly reactive toward nucleophiles. For example, o-quinones can
bind intracellular thiols such as cysteine and glutathione (GSH), and proteins having
cysteine residues (protein thiols). Since GSH acts as an antioxidant (e.g. GSH reacts
with H 2 O 2 to convert it to H 2 O), depletion of GSH by binding with o-quinones
would increase intracellular oxidative stress. Thus increased stress may stimulate
endoplasmic reticulum stress, leading to cell death through apoptotic and/or other
pathways. In addition, an elevated H 2 O 2 concentration may induce up-regulation of
tyrosinase activity [116], facilitating the production of o-quinones to cause cellular
stresses in an accelerated manner. It has also been reported that the o-quinone generated by RD oxidation, namely RD-quinone, forms a pheomelanin-like pigment as the
final product, through the binding of cysteine [117]. Pheomelanin is basically recognized as a pro-oxidant, which triggers ROS formation through photo-excitation and
then affects cellular oxidative stress [118–120].
As described above, the importance of immune response has been emphasized,
as well as cell injury caused by oxidative stress. From the viewpoint of the immune
system stimulation, the binding properties of o-quinones with protein thiols would
be important. As a unified explanation of the vitiligo mechanism, “Haptenation
theory” has been proposed [121]. This focuses on the fact that the generated oquinone is recognized as an antigen by binding with proteins, and that it induces
cellular immune responses. Although small chemical species alone cannot elicit
immune responses, some of them can form protein-bound complexes which are
recognized by immune cells. Such chemical species are called haptens. After binding
with proteins, as a possible mechanism to initiate immune responses, the complex
may be ubiquitinated to be degraded by proteasome and/or engulfed by autophagy.
The peptide fragments degraded here may be presented on the cellular surface with
major histocompatibility complex (MHC) class I and II (Note that melanocytes also
express MHC class II, as well as class I like antigen-presenting cells.), or be secreted
by releasing exosomes, which activate antigen-presenting cells like dendritic cells.
Through antigen presentation, activation of immune cells including CD8+ T-cells
may occur, thereby melanocyte-specific cytotoxic T-cells will emerge and proliferate.
Besides haptenation-associated immune sensitization, secretion of pro-inflammatory
cytokines IL-6, which is triggered by UPR activation as in 4-TBP, monobenzone, or
23
dose-dependent manner, which could be associated with the observed UPR activation
and be caused by induced apoptotic pathways [115]. From a chemical experiment,
the formation of super oxide radicals was also shown when RD was oxidated with
tyrosinase [108].
1.6.2 o-Quinones and Melanocyte-Specific Cytotoxicity
The above introduced cytotoxicity, in part, is presumably associated with the reaction between intracellular thiols and o-quinones generated by phenol or catechol
oxidation. (However, note that there is also a report showing that the cytotoxicity
of 4-TBP is not correlated with tyrosinase activity [112].) As previously stated,
o-quinones are highly reactive toward nucleophiles. For example, o-quinones can
bind intracellular thiols such as cysteine and glutathione (GSH), and proteins having
cysteine residues (protein thiols). Since GSH acts as an antioxidant (e.g. GSH reacts
with H 2 O 2 to convert it to H 2 O), depletion of GSH by binding with o-quinones
would increase intracellular oxidative stress. Thus increased stress may stimulate
endoplasmic reticulum stress, leading to cell death through apoptotic and/or other
pathways. In addition, an elevated H 2 O 2 concentration may induce up-regulation of
tyrosinase activity [116], facilitating the production of o-quinones to cause cellular
stresses in an accelerated manner. It has also been reported that the o-quinone generated by RD oxidation, namely RD-quinone, forms a pheomelanin-like pigment as the
final product, through the binding of cysteine [117]. Pheomelanin is basically recognized as a pro-oxidant, which triggers ROS formation through photo-excitation and
then affects cellular oxidative stress [118–120].
As described above, the importance of immune response has been emphasized,
as well as cell injury caused by oxidative stress. From the viewpoint of the immune
system stimulation, the binding properties of o-quinones with protein thiols would
be important. As a unified explanation of the vitiligo mechanism, “Haptenation
theory” has been proposed [121]. This focuses on the fact that the generated oquinone is recognized as an antigen by binding with proteins, and that it induces
cellular immune responses. Although small chemical species alone cannot elicit
immune responses, some of them can form protein-bound complexes which are
recognized by immune cells. Such chemical species are called haptens. After binding
with proteins, as a possible mechanism to initiate immune responses, the complex
may be ubiquitinated to be degraded by proteasome and/or engulfed by autophagy.
The peptide fragments degraded here may be presented on the cellular surface with
major histocompatibility complex (MHC) class I and II (Note that melanocytes also
express MHC class II, as well as class I like antigen-presenting cells.), or be secreted
by releasing exosomes, which activate antigen-presenting cells like dendritic cells.
Through antigen presentation, activation of immune cells including CD8+ T-cells
may occur, thereby melanocyte-specific cytotoxic T-cells will emerge and proliferate.
Besides haptenation-associated immune sensitization, secretion of pro-inflammatory
cytokines IL-6, which is triggered by UPR activation as in 4-TBP, monobenzone, or