Cytotoxicity of 6-biopterin to human melanocytes

(6R)5,6,7,8 tetrahydrobiopterin (6-BH4) is an important cofactor in the regulation of melanogenesis in melanocytes, where it controls: (a) the supply of L-tyrosine from L-phenylalanine via phenylalanine hydroxylase, and (b) regulates directly dopaquinone formation from L-tyrosine via tyrosinase. 6-BH4 undergoes redox-cycling by its oxidation to quinonoid dihydrobiopterin (qBH2) and to 6-biopterin through consecutive two electron oxidation reactions. The oxidized cofactor 6-biopterin (0.2 x 10(-6) M) is extremely cytotoxic to human melanocytes under in vitro conditions. Consequently, its reduction to 6-BH4 via q-BH2 is essential to melanocyte viability. In addition, the results herein show for the first time that human thioredoxin reductase has the capacity to reduce 6-biopterin to q-BH2 where further reduction to 6-BH4 follows via dihydropteridine reductase or reduced glutathione.