1.5 Biosynthesis of Pheomelanin—Reaction Process After Binding to Cysteine
21
In principle, tyrosinase may also be involved in the oxidation of cysteinyldopa. Nevertheless, tyrosinase activity is usually correlated with eumelanogenesis rather than pheomelanogenesis [100]. Therefore, tyrosinase-catalyzed oxidation of cysteinyldopa is not considered as a main factor of pheomelanin production. The evidence of the redox exchange reaction between dopaquinone and
cysteinyldopa was given by a pulse radiolysis experiment [100]. Pulse radiolysis of dopa with added 5-S-cysteinyldopa resulted in a unique transient profile
of light absorption, which is markedly different from the case without cysteinyldopa [100]. Although the absorption at 380 nm corresponds to both o-quinones
(i.e. dopaquinone and 5-S-cysteinyldopaquinone), the molar absorption coefficient
of 5-S-cysteinyldopaquinone is large enough for analyzing the redox exchange
reaction, which simultaneously forms the two quinones. After the immediate
formation of dopaquinone by pulse radiolysis, pseudo-first-order growth of 5-Scysteinyldopaquinone was recorded, demonstrating the redox exchange reaction
between dopaquinone and cysteinyldopa. In a similar manner, DHBTCA is oxidized
by dopaquinone in pheomelanogenesis [99]. Thus, dopaquinone is an important
oxidant in pheomelanogenesis.
Some of reported cysteinyldopa oxidation study were conducted with metal ions.
Aside from the possible oxidizing functions of metal ions, it has been pointed out that
metal ions may also significantly affect pheomelanogenesis as non-oxidative catalysts. For instance, Zn(II) suppresses the decarboxylation during the conversion of the
quinoneimine into 1,4-benzothiazine [101]. In contrast, Cu(II) and Fe(III) promotes
the decarboxylative pathway [102]. Furthermore, in the presence of Fe(III), increased
benzothiazole-moiety in pheomelanin was obtained [102]. These metal ions are relatively rich in melanosomes [103, 104]. Therefore, the above findings are an important
indication of physiologically relevant effects of metal ions on pheomelanogenesis.
This section reviewed the findings that have been revealed regarding pheomelanogenesis. These studies have established the overall picture of the reaction as shown
in Fig. 1.9. Chapter 3 of this book focuses on the mechanisms of the earliest process,
namely the formation of cysteinyldopa.
1.6 Melanin Chemistry in Relation to Melanocyte-Specific
Cytotoxicity
1.6.1 Cytotoxic Effects of p-Substituted Phenols
on Melanocytes
Due to the relatively low substrate specificity of tyrosinase in melanocytes, not only
the melanogenic starting substances, namely tyrosine and dopa, but also structurally
similar phenols and catechols are recognized by tyrosinase. This causes formation
of dopaquinone-like o-quinones, resulting in melanogenesis-like reactions.
21
In principle, tyrosinase may also be involved in the oxidation of cysteinyldopa. Nevertheless, tyrosinase activity is usually correlated with eumelanogenesis rather than pheomelanogenesis [100]. Therefore, tyrosinase-catalyzed oxidation of cysteinyldopa is not considered as a main factor of pheomelanin production. The evidence of the redox exchange reaction between dopaquinone and
cysteinyldopa was given by a pulse radiolysis experiment [100]. Pulse radiolysis of dopa with added 5-S-cysteinyldopa resulted in a unique transient profile
of light absorption, which is markedly different from the case without cysteinyldopa [100]. Although the absorption at 380 nm corresponds to both o-quinones
(i.e. dopaquinone and 5-S-cysteinyldopaquinone), the molar absorption coefficient
of 5-S-cysteinyldopaquinone is large enough for analyzing the redox exchange
reaction, which simultaneously forms the two quinones. After the immediate
formation of dopaquinone by pulse radiolysis, pseudo-first-order growth of 5-Scysteinyldopaquinone was recorded, demonstrating the redox exchange reaction
between dopaquinone and cysteinyldopa. In a similar manner, DHBTCA is oxidized
by dopaquinone in pheomelanogenesis [99]. Thus, dopaquinone is an important
oxidant in pheomelanogenesis.
Some of reported cysteinyldopa oxidation study were conducted with metal ions.
Aside from the possible oxidizing functions of metal ions, it has been pointed out that
metal ions may also significantly affect pheomelanogenesis as non-oxidative catalysts. For instance, Zn(II) suppresses the decarboxylation during the conversion of the
quinoneimine into 1,4-benzothiazine [101]. In contrast, Cu(II) and Fe(III) promotes
the decarboxylative pathway [102]. Furthermore, in the presence of Fe(III), increased
benzothiazole-moiety in pheomelanin was obtained [102]. These metal ions are relatively rich in melanosomes [103, 104]. Therefore, the above findings are an important
indication of physiologically relevant effects of metal ions on pheomelanogenesis.
This section reviewed the findings that have been revealed regarding pheomelanogenesis. These studies have established the overall picture of the reaction as shown
in Fig. 1.9. Chapter 3 of this book focuses on the mechanisms of the earliest process,
namely the formation of cysteinyldopa.
1.6 Melanin Chemistry in Relation to Melanocyte-Specific
Cytotoxicity
1.6.1 Cytotoxic Effects of p-Substituted Phenols
on Melanocytes
Due to the relatively low substrate specificity of tyrosinase in melanocytes, not only
the melanogenic starting substances, namely tyrosine and dopa, but also structurally
similar phenols and catechols are recognized by tyrosinase. This causes formation
of dopaquinone-like o-quinones, resulting in melanogenesis-like reactions.