Pheomelanin as a Binding Site for Drugs and Chemicals

Abstract

Certain drugs and chemicals, such as chloroquine, chlorpromazine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are bound to melanin and retained in pigment cells for long periods. This specific retention in pigmented tissues can cause adverse effects in the skin, eye, inner ear, and pigmented nerve cells of the substantia nigra of the brain. To date, all studies have been focused on eu- and neuromelanin. In the present study, we show that chloroquine, chlorpromazine, chlomipramine, paraquat, acridine orange, and nickel, which are bound to eumelanin, also bind to synthetic pheomelanin, but the binding to pheomelanin is lower. The binding varied with the cysteine content and pH, and the results indicate that the binding is complex and includes ionic interactions. In addition, we have shown that these substances also bind to synthetic thiourea-containing melanin, but to quite a low extent. We also present a microautoradiographic study on the binding of 14C-chloroquine to natural pheomelanin in vivo in yellow mice C57BL (Ay/a). Black (C57/BL) and albino (NMRI) mice were used as controls. The autoradiography demonstrated a pronounced uptake of chloroquine in the hair follicles and the dermal melanocytes in the ear of yellow mice, which was comparable to the corresponding accumulation of label in black mice. In the albino mouse, the uptake was lower and more homogeneously distributed in the skin. These results suggest that the toxicological risks of melanin-related adverse effects are applicable to persons with a high content of pheomelanin in the skin and hair.

Encapsulation of a reactive core in neuromelanin

“…The casing model (Fig. 1) is relevant in this respect in that pheomelanin is less efficient than eumelanin in binding drugs and metal ions (15). If pheomelanin were at the surface, the neuroprotective role of NM would not be expected.…”

Impact of Melanin on Microbial Virulence and Clinical Resistance to Antimicrobial Compounds

“…In addition to chloroquine, severe retinopathies can occur following melanin binding by chlorpromazine. Chloroquine also accumulates in dermal melanocytes and hair follicles (79), where it can occasionally cause irreversible hearing loss, tinnitus, and dizziness (44). Whereas hearing loss due to chloroquine is thought to be a result of effects on the eighth cranial nerve, quinine can accumulate in melanin in the stria vascularis of the cochlea and cause cellular degeneration (74).…”

The surface oxidation potential of human neuromelanin reveals a spherical architecture with a pheomelanin core and a eumelanin surface

“…In the regions of highest neuronal loss, namely the SN, studies have shown an increase in iron levels in the late stages of PD (10). Based on these observations, NM's role in avidly chelating redox-active metal ions, toxic organic compounds, and free radicals would serve as a protective role (11)(12)(13). Neurons that produce catecholamines (dopamine, norepinephrine, etc.)…”