Melanin Chemistry and Melanin Precursors in Melanoma

Abstract

T wo basic classes of melanin pigments are synthesized in mammals: brown-to-black eumelanin and yellow­ to-reddish pheomelanin (Fig 1) [1]. In melanocytes, a specific enzyme tyrosinase converts tyrosine to dopa and then to dopaquinone, which is cyclized to leuco­ dopachrome in a rapid, nonenzymatic reaction. This compound is oxidized to dopachrome, a red pigment, which in turn gives 5,6-di­ hydroxyindole (5,6DHI) by decarboxylation and to some extent 5,6-dihydroxyindole-2-carboxylic acid (5,6DHI2C) by rearrange­ ment [2]. These dihydroxyindoles are highly reactive and are fur­ ther oxidized to give rise to a eumelanin polymer. If dopaquinone encounters cysteine or glutathione, pheomelanin is formed via cys­ teinyldopas. Among these melanin precursors, 5-S-cysteinyldopa (5-S-CD), a major isomer of cysteinyldopas, has been shown to reflect the metastasis of melanoma [3]. Until recently, it was generally accepted that eumelanin is made mostly from 5,6DHI, but not from 5,6DHI2C. However, the fol­ lowing evidence has accumulated in recent years indicating the significance of 5,6DHI2C as an alternative precursor of eumelanin: 1) urine from melanoma patients contains high levels of the 0methyl derivatives of 5,6DHI2C in addition to the derivatives of 5,6DHI [4]; 2) divalent cations such as Cu2+ catalyze the conversion of dopachrome to 5,6DHI2C but not to 5,6DHI [5], and these ions are rich in melanocytes [6]; 3) the dopachrome conversion factor found by Pawelek's group also catalyzes the conversion of do­ pachrome to 5,6DHI2C [7] but not to 5,6DHI, as previously pro­ posed [8]. This review describes the results of our recent studies dealing with the melanin chemistry and melanin precursors in melanoma.