Identification and biophysical characterization of two intralysosomal pigments with free-radical properties and their synthetic models: Human neuromelanin and the minocycline-induced thyroid pigment
Enochs, William Scott
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Permalink
https://hdl.handle.net/2142/20959
Description
Title
Identification and biophysical characterization of two intralysosomal pigments with free-radical properties and their synthetic models: Human neuromelanin and the minocycline-induced thyroid pigment
Author(s)
Enochs, William Scott
Issue Date
1992
Doctoral Committee Chair(s)
Swartz, Harold M.
Department of Study
Biophysics and Computational Biology
Discipline
Biophysics
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Animal Physiology
Biophysics, General
Language
eng
Abstract
Melanins are complex, incompletely understood polymeric pigments which uniquely contain a stable population of organic free radicals amenable to study by electron paramagnetic resonance (EPR, or equivalently, electron spin resonance, ESR) spectroscopy. In contrast to the usual histochemical tests, a set of EPR criteria has been established for the unambiguous identification of melanin; however, their practical application often is hampered by a lack of standardized materials and methods. A standardized EPR test for melanin therefore has been developed, tested successfully, and used to identify and characterize two intralysosomal pigments with paramagnetic properties: human neuromelanin, a natural pigment of the substantia nigra presumed to derive from the neurotransmitter dopamine (DA), and a pigment induced in human and canine thyroids by administration of the tetracycline antibiotic minocycline. Using bovine eye melanin as a control, neuromelanin is found to be an atypical melanin that is poorly modeled by synthetic DA melanin, whereas the thyroid pigment does not qualify as a melanin but is similar to a pigment formed by autooxidation of minocycline in vitro. Other results show that these two natural pigments contain bound paramagnetic metal ions in situ and that incubation in strong acid at room temperature during the purification of natural pigments is well-suited for EPR purposes in general. Using synthetic DOPA melanin as a control, several new methodological approaches involving X-band EPR also have been used in comprehensive characterizations of synthetic DA melanin and the synthetic minocycline pigment. Many of the nonparamagnetic and paramagnetic properties of synthetic melanins and related pigments have been explained by postulating that they have a partial tertiary structure in solution. Compared to DOPA melanin, DA melanin is fundamentally similar but has several differences which have been attributed mainly to its larger fraction of uncyclized subunits. By contrast, the minocycline pigment is fundamentally unique, appears to be a heterogeneous copolymer of native minocycline and its oxidation products, and has distinctive paramagnetic properties which have been accounted for by postulating the coexistence of stable subpopulations of semiquinone imines and more typical semiquinones. Finally, based on the known reactivities of melanin with O$\sb2$ and its reduced forms in vitro, a general hypothesis is presented for a new category of pathophysiologic phenomena involving the deposition and potential cytotoxicity of intralysosomal pigments with paramagnetic properties. This supports recent suggestions that neuromelanin has a role in the pathogenesis of Parkinson's disease and indicates that the minocycline-induced thyroid pigment may not be innocuous.
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