Melanin and neuromelanin binding of drugs and chemicals: toxicological implications.
Melanin is a polyanionic pigment that colors, e.g., the hair, skin and eyes. The pigment neuromelanin is closely related to melanin and is mainly produced in specific neurons of the substantia nigra. Certain drugs and chemicals bind to melanin/neuromelanin and are retained in pigment cells for long periods. This specific retention is thought to protect the cells but also to serve as a depot that slowly releases accumulated compounds and may cause toxicity in the eye and skin. Moreover, neuromelanin and compounds with high neuromelanin affinity have been suggested to be implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the etiology of Parkinson's disease (PD). Epidemiologic studies implicate the exposure to pesticides, metals, solvents and other chemicals as risk factors for PD. Neuromelanin interacts with several of these toxicants which may play a significant part in both the initiation and the progression of neurodegeneration. MPTP/MPP(+) that has been casually linked with parkinsonism has high affinity for neuromelanin, and the induced dopaminergic denervation correlates with the neuromelanin content in the cells. Recent studies have also reported that neuromelanin may interact with α-synuclein as well as activate microglia and dendritic cells. This review aims to provide an overview of melanin binding of drugs and other compounds, and possible toxicological implications, with particular focus on the CNS and its potential involvement in neurodegenerative disorders.
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 171 76, Stockholm, Sweden. Oskar.Karlsson@ki.se.|Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden. Oskar.Karlsson@ki.se.
Oskar
O
Karlsson
Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
Nils Gunnar
NG
Lindquist
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000096:biosynthesis
D014150:Antipsychotic Agents; D004785:Environmental Pollutants; D008543:Melanins; D051844:alpha-Synuclein; C014121:neuromelanin
ALS/PDC; BMAA; MPTP; Neuromelanin; Parkinson’s disease; Pesticides; Retinopathy