1. ^*Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, West Yorkshire, UK
2. ^†Institute for Pigmentary Disorders in Association with the Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany

Correspondence: K.U. Schallreuter, Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, West Yorkshire BD7 1DP, UK. Email: K.Schallreuter@bradford.ac.uk

Received 12 July 2003; Revised 26 August 2003; Accepted 10 September 2003; Published online 12 February 2004.

Abstract

To date there is ample evidence that patients with vitiligo accumulate millimolar concentrations of hydrogen peroxide (H₂O₂) in their epidermis as well as in their blood lymphocytes/monocytes. Several enzymes are affected by this H₂O₂ including catalase, glutathione peroxidase, and 4-carbinolamine dehydratase. The latter enzyme disrupts the recycling of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH₄) for the aromatic amino acid hydroxylases as well as the nitric oxide synthases. In this report we have elucidated the influence of H₂O₂ on dihydropteridine reductase (DHPR), the last enzyme in the 6BH₄-recycling process. Here we show for the first time that concentrations of less than 30 M H₂O₂ increase DHPR activities, whereas levels greater than 30 M H₂O₂ deactivate the enzyme based on the oxidation of Met¹⁴⁶ and Met¹⁵¹ in the sequence, consequently leading to disruption of the NADH-dependent enzyme active site. This oxidation was confirmed by Fourier transform-Raman spectroscopy yielding the expected SO band at 1025 cm^-1 characteristic of methionine sulfoxide. Hence these results unmasked a novel regulatory mechanism for DHPR enzyme activity. Moreover, we also demonstrated that DHPR activities in whole blood of patients with vitiligo are significantly decreased in untreated patients, whereas activities are normalized after removal of epidermal H₂O₂ with a topical pseudocatalase (PC-KUS). Taken together, these new data add more evidence to a systemic involvement of H₂O₂ in the pathomechanism of vitiligo.