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 (H2O2) 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 (6BH4), has extremely low activities in these patients concomitant with a build-up of the abiogenic 7-isomer (7BH4), leading to competitive inhibition of epidermal phenylalanine hydroxylase. A topical substitution for the impaired epidermal catalase with a pseudocatalase effectively removes epidermal H2O2, yielding a recovery of epidermal 4a-OH-tetrahydrobiopterin dehydratase activities and physiologic 7BH4 levels in association with successful repigmentation demonstrating recovery of the 6BH4 recycling process. Examination of recombinant enzyme activities, together with 4a-OH-tetrahydrobiopterin dehydratase expression in the epidermis of untreated patients, identifies H2O2-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 H2O2 inactivation of the important 6BH4 recycling process. Based on this observation, we suggest that H2O2 derived from various sources could be a general mechanism in the regulation of all 6BH4-dependent processes.