Metabolic interference of melanogenesis in pigment cells.

Biosynthesis of pigment melanin in pigment cells (melanocytes, nevus cells, melanoma cells) constitutes a distinctive but integrated part of intracellular metabolism. Although the melanin formation takes place in specialized compartments (melanosomes), these structures are not fully "leak-proof" and, as a consequence, the reaction products of melanogenesis have an opportunity to interact with different metabolic processes. This can be of particular importance when the melanogenesis is stimulated (e.g. by UV radiation) and when the integrity of melanosomes and/or their limited membranes is disturbed. From the toxicologic viewpoint melanogenesis represents an unique metabolic burden for the cell and this fact can have consequences for cellular defence systems. For instance, the conjugation of melanogenic precursors present in cytoplasm with glutathione or cysteine may reduce the availability of the thiocompounds for other necessary protective reactions. For the same reason, in melanin-producing cells there is an increased need for detoxification of the reactive intermediates by O-methylation. This reaction catalyzed by catechol-O-methyl-transferase may lead to concentration changes of methyl donor S-adenosylmethionine and the reaction product S-adenosylhomocysteine. As a consequence, decreased S-adenosylmethionine/S-adenosylhomocysteine ratio (so-called "methylation ratio") is known to have profound inhibitory effect on methylation processes inclusive DNA methylation. Although still very speculative, this situation might very well lead to the generation of CpG mutations and (due to DNA hypomethylation) to activation of silent (onco)genes.