The polymerization of melanin: a poorly understood phenomenon with egregious biological implications.

Several hypotheses have explicitly implicated the role of an altered redox status of melanin in the aetiology of melanoma and macular degeneration. The balance between the intrinsic anti-oxidant and pro-oxidant properties of melanin is lost, resulting in an altered redox phenotype. We propose that such an alteration of the redox status of melanin may arise, in part, due to suboptimal conditions for the effective polymerization of melanin precursors.

Hypoxia-targeted bioreductive tyrosine kinase inhibitors with glutathione-depleting function.

Tyrosine kinase inhibitors may serve as ligands for kinases that are involved in normal cell differentiation or repair, thereby leading to toxicity. It may be possible to target such inhibitors to tumor cells by coupling them to hypoxia-activated bioreductive molecules. Such coupling can utilize or incorporate bonds that have a propensity to be preferentially oxidized by thiols such as intracellular glutathione (GSH).

Melanization and phagocytosis: implications for age related macular degeneration.

Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) may also be implicated in the downregulation of rod outer segment (ROS) phagocytosis by the RPE. Melanization activating pathways may also modulate oxygen consumption by the photoreceptors, apolipoprotein E4 levels, and the rate of photoisomerization events such that the net effect may be a reduction in drusen and/or lipofuscin accumulation. An increase in melanin at the apical microvilli of the RPE may shield ROS from light thereby contributing in part to the decrease in the rate of ROS phagocytosis.

Melanin aggregation and polymerization: possible implications in age-related macular degeneration.

The state of aggregation of the polymer melanin may determine its propensity to act either as an antioxidant or as a pro-oxidant. Age-related alterations in its state of aggregation are suggested to alter the degree of polymerization so as to confer increased pro-oxidant propensity to the melanin polymer. Degradative processes in/of melanosomes and lysosomes in the retinal pigment epithelium (RPE) appear to be intimately connected so that they may involve exchange of contents between these two organelles.

Ocular melanogenesis: the role of antioxidants.

Given the propensity of a large number of melanogenic pathways that can be modulated by cellular redox status, a causal role of the deficiency of ocular pigments such as melanin in the pathogenesis of age-related macular degeneration and evidence that melanin production does occur in the adult eye, it seems not improbable that antioxidants (or agents that modify cellular redox status) may have melanin stimulatory (or inhibitory) effects that are superimposible on their effects as mere free radical scavengers. More empirical studies are needed to investigate this phenomenon so that antioxidant therapy may prove more beneficial to patients with ocular degenerative diseases.