Current Update and Trends in Melanin Pigmentation and Melanin Biology
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Certain aspects of current progress in melanin biology and its possible clinical relevances are reviewed with emphasis on some of our recent research activities. The important aspects discussed are (a) the biological properties of melanin pigments and their relevance to biological functions, (b) functional interaction of melanogenic/melanogenesis-associated genes in melanin biosynthesis process (melanogenesis, and (c) the targeting of proteins involved in melanogenesis and assembly by melanosomal proteins. Upon exposure to UV light radiation (UVR), melanin pigments revealed two distinct photobiological reactions, <i>i.e.</i> photoprotective and phototoxic reactions. The precursor intermediate of brown-black eumelanin, 5-6-dihydroxyindole, appears to possess the most potent photoprotective (antioxidant) property. Eumelanin pigment also had some antioxidant property. Similarly, yellow-red pheomelanin and its precursor intermediate, 5-S-cysteinyldopa also revealed some antioxidant property, but they became prooxidant in the presence of the ferric iron upon exposure to UVR. Melanosomes are known to possess several metal ions including Fe<sup>2+</sup>, Fe<sup>3+</sup>, Cu<sup>2+</sup> and Zn<sup>2+</sup>. In addition, upon exposure to UV-light, there is an increase in ferric/ferrous iron in the skin. Therefore, in the <i>in vivo</i> system, pheomelanin intermediate, 5-S-cysteinyldopa, may show significant prooxidant property in conjunction with metal ions (e.g. Fe<sup>2+</sup>, Fe<sup>3+</sup>). When atypical moles (previously called dysplastic nevi) were analysed chemically for quantitative and qualitative properties of melanin pigment, they revealed a high ratio of pheomelanin/eumelanin content. This finding may partly explain our clinical observation that these moles are frequently the precursors of malignant melanoma and that the intermittent heavy exposure of UVR can be the major direct cause of their transformation. How, then, the melanosomal compartment, where active new melanin synthesis occurs after exposure to UVR, is protected from the cytotoxicity of melanin precursor intermediates. To study this question, two major experiments were conducted; (a) expression of melanogenesis-associated genes upon exposure of melanocytes to UVR and (b) transfection of cDNAs from the melanogenesis associated genes. There was coordinated gene expression (mRNA) of tyrosinase and tyrosinase-related protein, TRP-1 and this coordinated gene expression was also accompanied by the upregulation of LAMP-1 (lysosome-associated membrane protein-1). Furthermore, human tyrosinase and TRP-1 mRNAs were expressed successfully in individual transfectants or co-transfectants of cDNAs from the two genes. Co-transfectants of human tyrosinase and TRP-1 cDNAs produced many lysosomal granules and melanin-containing granules, melanosomes. LAMP-1 gene was upregulated simultaneously in co-transfectants of tyrosinase and TRP-1, but not in individual transfectants of the two genes. TRP-1 and LAMP-1 gene products were transferred from Golgi complexes to melanosomes. LAMP-1 gene products stimulated by TRP-1 and tyrosinase genes may prevent programmed death of melanocytes due to cytotoxic melanin precursor intermediates by coating the inner surface of melanosomal membrane through the N- and O-linked oligosaccharide moieties of LAMP-1 which have been suggested to protect lysosomes from the action of hydrolytic enzymes.
- Keio J. Med.
Keio J. Med. 44(1), 9-18, 1995-03-01
The Keio Journal of Medicine