Epidermal H2O2 Accumulation Alters Tetrahydrobiopterin (6BH4) Recycling in Vitiligo: Identification of a General Mechanism in Regulation of All 6BH4-Dependent Processes?

Abstract

It has been shown in vivo that patients with the depigmentation disorder vitiligo accumulate hydrogen peroxide (H(2)O(2)) accompanied by low catalase levels and high concentrations of 6- and 7-biopterin in their epidermis. Earlier it was demonstrated that epidermal 4a-OH-tetrahydrobiopterin dehydratase, an important enzyme in the recycling process of 6(R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH(4)), has extremely low activities in these patients concomitant with a build-up of the abiogenic 7-isomer (7BH(4)), leading to competitive inhibition of epidermal phenylalanine hydroxylase. A topical substitution for the impaired epidermal catalase with a pseudocatalase effectively removes epidermal H(2)O(2), yielding a recovery of epidermal 4a-OH-tetrahydrobiopterin dehydratase activities and physiologic 7BH(4) levels in association with successful repigmentation demonstrating recovery of the 6BH(4) recycling process. Examination of recombinant enzyme activities, together with 4a-OH-tetrahydrobiopterin dehydratase expression in the epidermis of untreated patients, identifies H(2)O(2)-induced inactivation of this enzyme. These results are in agreement with analysis of genomic DNA from these patients yielding only wild-type sequences for 4a-OH-tetrahydrobiopterin dehydratase and therefore ruling out the previously suspected involvement of this gene. Furthermore, our data show for the first time direct H(2)O(2) inactivation of the important 6BH(4) recycling process. Based on this observation, we suggest that H(2)O(2) derived from various sources could be a general mechanism in the regulation of all 6BH(4)-dependent processes.

A novel mechanism in control of human pigmentation by β-melanocyte-stimulating hormone and 7-tetrahydrobiopterin

“…High 7BH 4 levels were also found in the epidermis of patients with the depigmentation disorder, vitiligo (Schallreuter et al 1994a,b). In the latter case, it was shown that these high levels are based on deactivation of the enzyme PCD due to accumulation of H 2 O 2 in the 10 3 M range (Schallreuter et al 2001). Taken together, a role for 7BH 4 in the pathophysiology of these two diseases has been proved.…”

A Critical Appraisal of Vitiligo Etiologic Theories. Is Melanocyte Loss a Melanocytorrhagy?

“…1). Complex interactions between pterin metabolism, melanin and catecholamine synthesis may be abnormally mediated by H 2 O 2 in NSV (70). Based on recent studies of mononuclear cells in the sera of patients with NSV, Picardo's group suggested that mitochondria might be an unifying target of reactive oxygen species generation, cytokine production, catecholamine release, alteration of Ca 2+ metabolism leading to melanocyte loss (59).…”

Photosensitization of peptides and proteins by pterin derivatives

“…In vitiligo, a skin disorder characterized by a defective protection against UV radiation due to the acquired loss of constitutional pigmentation [19], H 4 Bip metabolism is altered [20]. Dihydro and oxidized pterin derivatives accumulate in the affected tissues at concentrations that are significantly higher than those reported for healthy cells [20,21]. Although intracellular concentrations were not determined, it can be assumed that pterins can reach any cellular compartment since these compounds can freely cross phospholipid membranes [22].…”