Dynamics of melanogenesis intermediates.

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.