The plasma soluble
melanins (PSM) form spontaneously in vitro and in vivo and their formation involves oxidative polymerization and copolymerization of
dopa,
catecholamines,
homogentisic acid,
3-hydroxyanthranilic acid,
p-aminophenol,
p-phenylenediamine, and other end(ex)ogenous ortho and para polyhydroxy-, (poly)hydroxy(poly)amino- and polyamino-phenyl compounds. The build up of PSM is visible within 2-3 h after the start of incubation at 37 degrees C with 1 mg/ml of plasma. PSM also form similarly in blood and these processes cause
hemolysis. The mean quantity of PSM in normal human plasma is 1.61+/-0.1 (S.D.) mg/ml (n = 20) and in normal human urine is 1.1+/-1.2 g/24 h collection (n = 8). They contribute to the yellow color of plasma and urine.
Antioxidants delay the formation of PSM. The deposited
melanins also form from these precursors. Reactive
oxygen side products (ROSP) are generated during and after melanogenesis.
Melanins in vivo are generally associated with
proteins or with
proteins and
lipids. The PSM-
protein-
lipid complexes are called plasma soluble lipofuscins (PSL), because they have histochemical and fluorescence properties similar to those of solid lipofuscins. The soluble and deposited
melanins (
SDM) and their intermediates have similar toxic chemical reactivities. The oxidizing quinoid (they can produce partially and completely substituted conjugates) and the semiquinoid
free radical intermediates are also moieties in most human
melanin structures. Soluble
melanins formed from
dopa, or
dopamine, or
norepinephrine in weak alkaline
solution have been shown to be toxic to human CD4+ lymphoblastic cells (MT-2) at higher than 10 microg/ml concentrations.
Alkaptonuria with high levels of
homogentisic acid in the plasma is a potentially fatal disease, exhibiting the toxic effects of the
homogentisic acid melanin (soluble and deposited), its intermediates and the ROSP. Patients with
alkaptonuria develop
arthritis and often suffer from other diseases too, including
cardiovascular disease (frequent cause of death) and
kidney disease.
Pheochromocytoma, with high levels of
catecholamines in the plasma is another potentially fatal disease. The
catecholamine PSM of
pheochromocytoma have very light yellow or practically no colors, due to the concentrations and chemical structures.
Pheochromocytomas can cause
hypertension,
cardiovascular disease (frequent cause of death),
kidney disease,
stroke,
cancer,
amyloid formation and can mimic many other diseases, including
acute pancreatitis,
carcinoid,
neuroblastoma,
psychiatric illness,
hypercalcemia,
retinal vascular lesions, and
diabetes mellitus.
Pheochromocytoma is potentially fatal even in patients without
hypertension. Following
trauma and surgery, heavily pigmented eyes are
apt to experience greater
inflammation than lightly pigmented eyes. In
Parkinson's disease those neurons are lost first in the substantia nigra and locus ceruleus which contain the greatest amounts of neuromelanins. The
antihypertensive alphamethyldopa causes Parkinson's syndrome. It forms PSM in a short time in vitro. The side effects of
L-dopa (immobility episodes alternate with normal or
involuntary movements; psychotic abnormalities) suggest that the
SDM, their intermediates and the ROSP present naturally in vivo are involved in the cause of
Parkinson's disease and
Alzheimer's disease. There is a large overlap between these two diseases. (ABSTRACT TRUNCATED)