An increased release of catecholamines from the autonomic nerve endings in the microenvironment of melanocytes in the affected skin areas has been suggested, since changes in the content of epinephrine and norepi- nephrine in the blood of patients with vitiligo have been measured (Durneva 1973). More recently, the urine levels of homovanillic acid (HVA) and vanillmandelic acid (VMA) from dopamine and from norepineph- rine and epinephrine, appeared to be elevated in subjects affected either with the early active phase or with the progression of vitiligo. A higher, although not significant, concentration of these neurotransmitters was 145
CHAPTER 18
Neural Pat hogenesis
CHAPTER 18
Neural (Orecchia et al. 1994).
Pat hogenesis
found also in the plasma of patients with generalized and acrofacial vitiligo These neurotransmitters are known for having toxic properties by:
1 interacting with cellular sulphydryl groups, 2 inhibiting enzyme activities,
3 impairing some mitochondria1 energy processes such as calcium uptake and
4 forming cytotoxic products such as free radicals, orthoquinones and hydroxylated indoles (Bindoli et al. 1992).
Besides a direct cytotoxicity, they could have an indirect action by acti- vating a-receptors of skin arterioles causing a severe vasoconstriction.
Hypoxia produces toxic oxygen radicals (Morrone et al. 1992).
An enormously high concentration of norepinephrine and its metabolites in vitiligo has been recently related to a decrease of phenylethanolamine-N-methyl transferase activity (PNMT) and an increased activity of tyrosine hydroxylase (TH), the key enzyme in the cate- cholamine pathway, producing L-dopa from L-tyrosine (Schallreuter et al.
1994b). The rate-limiting cofactor/electron donor for TH is (6R)-5,6,7,8- tetrahydrobiopterin (6-BH4), which is increased due to a decreased 4a- hydroxy-6-BH4 dehydratase (DH) activity (Schallreuter et al. 1994a). The presence of this nonenzymatic by-product in epidermis is supposed to initi- ate the process of depigmentation in the vitiligo, by blocking the supply of L-tyrosine either directly in the melanocytes or from the surrounding basal keratinocytes. These alterations are said to produce melanocyte dysfunc- tion or injury (see Chapter 19).
A derangement of the enzymes dealing with catabolism of adrenergic transmitters has been reported, namely, catechol-o-methyltransferase (COMT) and monoamino oxidase (MAO-A). COMT normally prevents the formation of toxic orthoquinones during melanin synthesis. Epidermal homogenates from vitiligo patients express a higher COMT activity, proba- bly induced in the tissues by elevated levels of catecholamines secreted by keratinocytes or by nerve endings. Toxic products may be damaging to the melanocytes because of their slow turnover rate (Le Poole et al. 1994).
COMT activity is also related to decreased Ca,+ concentrations in vitiligo for a defective calcium uptake in keratinocytes (Schallreuter & Pittelkow 1988) and may contribute to depigmentation by decreasing the amount of pre- cursor molecules available for melanin formation. This effect can be fur- ther aggravated by an increased expression of P,-adrenoreceptors (Schallreuter et al. 19931, which regulate intracellular calcium concentra- tions (Koizumi et al. 1991) and are increased in numbers at low calcium levels (Schallreuter et al. 1993).
An alteration of calcium metabolism in vitiligo has been recently confirmed by a study on defective calcium transport in vitiligi- nous melanocytes (Schallreuter-Wood et al. 1996) correlating with reduced thioredoxin reductase/thioredoxin. Thioredoxin functions as an allosteric inhibitor of tyrosinase through an increase of the concentration of
hydrogen peroxide in the epidermis of vitiligo patients (Schallreuter et al. 1991).
A consequence of increased norepinephrine appears to be the induction of another catecholamine degrading enzyme, the monoamino oxidase (MAO-A) (Bindoli et al. 1992). The increased MAO-A activity favours the formation of toxic levels of hydrogen peroxide (Schallreuter et al. 1996). The damage to the melanocytes is not buffered by the low catalase activity (Schallreuter et al. 1996).
Since stress also influences the catecholamine secretion, a trial correlat- ing their levels with the personality structure of vitiligo patients has been made (Salzer & Schallreuter 1995), correlating the neurotransmitter pat- terns with the diagnosis, treatment, and pathophysiology of several neuro- genetic disorders (Goldstein et al. 1996).
The effect of acetylcholine, another neurotransmitter, was studied. The acetylcholine esterase activity is lowered in vitiliginous skin during depig- mentation, giving further support to the neural influences on the pathogen- esis of vitiligo (Iyengar 1989).
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19: Biochemical Theory of Vitiligo: a Role of Pteridines in Pigmentation
KARIN U . SCHALLREUTER, WAYNE D. BEAZLEY A N D J O H N M . W O O D
Introduction
Vitiligo is an acquired idiopathic depigmentation disorder affecting 0.54%
of the world population (Ortonne & Bose 1993). A significant decrease in the numbers of functioning epidermal melanocytes or their complete absence in the white skin of affected individuals has been described (Gokhale &
Mehta 1983; Le Poole et al. 1993a, Chapters 1 and 2). There have been several hypotheses proposed in the past but none of them seems to cover the entire spectrum of this enigmatic disorder.
The clinical hallmarks of vitiligo are white patches together with normal pigmented skin in the same individual (Fitzpatrick et al. 1979). The diagno- sis is usually made by eye because the distribution and localization is, in the majority, characterized by symmetrical appearance. However, there are also clinical forms of the disease which can mimic other clinical leukodermas (Ortonne & Bose 1993). A very simple clinical observation has been useful to overcome this difficulty. We suggest that, upon Wood’s light examination at 351nm the clinically white skin of vitiligo shows a characteristic yellow/green or bluish fluorescence, whereas we propose that other leuko- dermas lack this phenomenon (Schallreuter et al. 1994b, c) (Fig. 19.1). We attribute this fluorescence originates in the accumulation of two different oxidized pteridines, 6-biopterin with a bluish fluorescence and 7-biopterin, its isomer, with yellow/green fluorescence (Schallreuter et al. 199413, c).