REGULATION OF MELANIN BIOSYNTHESIS IN THE HUMAN EPIDERMIS BY TETRAHYDROBIOPTERIN

The participation of (6R) 5,6,7,8-tetrahydrobiopterin (6-BH4) in regul ating the tyrosine supply for melanin biosynthesis was investigated by the examination of human keratinocytes, melanocytes, and epidermal su ction blisters from normal human skin and from patients with the depig mentation disorder vitiligo. Cells, as well as total epidermis, contai ned high phenylalanine hydroxylase activities and also displayed the c apacity to synthesize and recycle 6-BH4, the essential cofactor for th is enzyme. In vitiligo, 4a-hydroxy-BH4 dehydratase activity was extrem ely low or absent, yielding an accumulation of the nonenzymatic by-pro duct 7-tetrahydrobiopterin (7-BH4) at concentrations up to 8 x 10(-6) M in the epidermis. This by-product is a potent competitive inhibitor in the phenylalanine hydroxylase reaction with an inhibition constant of 10(-6) M. Thus, 6-BH4 seems to control melanin biosynthesis in the human epidermis, whereas 7-BH4 may initiate depigmentation in patients with vitiligo.