The course of melanogenesis in (malignant) melanocytes is determined by several relatively independent metabolic processes such as
tyrosine uptake and compartmentation, the activity of
tyrosinase, and the capacity of melanosomes to produce and store
melanin. There is experimental evidence that
tyrosine is transported across the cell membrane with a Na(+)-independent L transport system.
Tyrosine designated for melanogenesis is probably localized in compartments different from those for
protein synthesis. The maturation and subsequent activation of
tyrosinase occurs primarily in the Golgi-associated endoplasmatic reticulum and coated vesicles. In these locations, the interaction between
tyrosine and
tyrosinase has some limitations because no
melanin polymer can be detected in these structures. Nevertheless, the coated vesicles were shown to contain unpolymerized monomeric indols. Individual skin types differ in their ability to produce mature, fully pigmented, melanosomes. Whereas
eumelanin content in melanocytes corresponds to the phenotypic appearance of the skin, the formation of
pheomelanin varies considerably. Precursors of
pheomelanin, such as
glutathione and
cysteine, are responsible for scavenging potentially toxic quinoid products of melanogenesis that escape from melanogenic compartments. Pheomelanogenesis can therefore be considered as one of the protective mechanisms of melanocytes. Significant leakage of reactive intermediates of melanogenesis may occur from aberrant melanosomes and explain the frequent incidence of
necrosis in
melanoma tissue. The presence of O-methylated derivatives of
5,6-dihydroxyindole (5,6DHI) and
5,6-dihydroxyindole-2-carboxylic acid (5,6DHI2C) in medium of
melanoma cell cultures gives evidence of intracellular O-methylating ability. The O-methylation of o-dihydroxyphenols and indols by
catechol-O-methyltransferase localized in microsomes and cytoplasma prevents their oxidation to reactive
quinones. It is suggested, however, that this protective mechanism can be unreliable because
catechol-O-methyltransferase can be inactivated by its oxidated substrates.