5,6-Dihydroxyindole is a melanin precursor showing potent cytotoxicity

Abstract

WE have previously suggested that factors which regulate the proliferation and pigmentation of Cloudman S-91 mouse melanoma cells share common biochemical pathways^1,2. Our conclusion was based on the following observations: (1) most mutant cells selected for their ability to grow in culture medium containing melanocyte-stimulating hormone (MSH) show an altered ability to produce pigment¹, and (2) tyrosinase is activated in response to elevated levels of cyclic AMP in a reaction apparently mediated by a cyclic AMP-dependent protein kinase³. This same protein kinase has been implicated as a positive regulator in the proliferation of Cloudman cells⁴. In addition, we found that some precursors of melanin are cytotoxic and that cells actively producing melanin run the risk of self-destruction through a build-up of these precursors. We have previously shown that pigmented cells are killed as a result of exposure to excess tyrosine or dihydroxyphenylalanine (dopa) in the culture medium^2,5. It has since been demonstrated that actively melanising cells release a cytotoxic agent into their culture medium⁶. Here we present further evidence for the cytotoxicity of melanin precursors and show that 5,6-dihydroxyindole is one of the toxic compounds in the melanin biosynthetic pathway.