DEFECTIVE TETRAHYDROBIOPTERIN AND CATECHOLAMINE BIOSYNTHESIS IN THE DEPIGMENTATION DISORDER VITILIGO

Patients with the depigmentation disorder vitiligo lack the capacity t o synthesize the melanins from L-tyrosine via the essential activity o f tyrosinase. The aim of this study has been to examine both the suppl y of the substrate (L-tyrosine) and the regulation of tyrosinase in th e epidermis of subjects with vitiligo. Patients with this depigmentati on disorder have a 3- to 5-fold increase in GTP-cyclohydrolase I activ ity leading to an excessive de novo synthesis of (6R)5,6,7,8 tetrahydr obiopterin (6-BH4). Continuous production of 6-BH-(4) leads to: (1) an accumulation of the non-enzymatic byproduct 7-tetrahydropterin (7-BH4 ) in the epidermis, and (2) increased synthesis of the catecholamines in keratinocytes, leading to an excess of norepinephrine in both the p lasma and urine of these patients. In vitiligo, the time-dependent pro duction of 7-BH4 is caused by decreased 4a-hydroxytetrahydrobiopterin dehydratase activity; the essential enzyme for recycling and maintaini ng normal levels of 6-BH-(4). In the epidermis and in cultured melanoc ytes, 7-BH4 is a potent competitive inhibitor of phenylalanine hydroxy lase (K-i = 10(-6) M) and its accumulation in the epidermis of patient s with vitiligo blocks the supply of L-tyrosine from L-phenylalanine. 4a-hydroxytetrahydrobiopterin dehydratase has a dual function as the a ctivator/dimerization catalyst for the transcription factor hepatocyte nuclear factor I (HNF-I). HNF-I binds to a 16-base inverted palindrom e which seems to be present on the promoters of both the tyrosinase an d phenylethanolamine-N-methyl transferase (PNMT) genes. Therefore, def ective 4a-hydroxytetrahydrobiopterin dehydratase in vitiligo influence s not only the supply of L-tyrosine but also the transcription of the tyrosinase gene in melanocytes. Furthermore, a similar transcriptional regulation of the PNMT gene in keratinocytes offers a possible explan ation for the accumulation of norepinephrine in these patients.