Human Iridal Stroma Melanosomes of Varying Pheomelanin Contents Possess a Common Eumelanic Outer Surface

Uveal melanosomes originating in the iridal stroma contain both black (eumelanin) and red (pheomelanin) pigment. Recent studies reveal that the eumelanin/pheomelanin ratio varies with iris color, with lower ratios being observed for lighter color (hazel, blue) irides. This is of great interest because the epidemiology of uveal melanomas also indicates an increased incidence for lighter-colored irides. Herein, we examine human iridal stroma melanosomes from dark brown and blue-green irides, which are characterized by a eumelanin/pheomelanin ratio of 14.8 and 1.3, respectively. Atomic force microscopy reveals that the melanosomes extracted from these different colored irides have a similar size and overall morphology. Studies of the surface ionization potentials reveal that the surface of these melanosomes is pure eumelanin, despite the significant difference in their overall pigment composition. These data indicate that the pheomelanin present in the melanosome is encased by eumelanin, providing support for the "casing model" architecture of mixed melanins advanced from kinetic studies of the early steps in the melanogenesis pathway. Because of the different bulk composition, these results indicate that the thickness of the outer eumelanin coating decreases as the iride color lightens. Oxidative damage to the melanosome surface is therefore more likely to enable access to the photoreactive pheomelanin in the lighter irides than that in the eumelanin-rich dark irides. This provides new insights into the potential contribution of iridal stroma melanosomes both to inducing oxidative stress and to accounting for the observed iris-color-dependent epidemiology of uveal melanoma.