Down-regulation of GTP cyclohydrolase I and tetrahydrobiopterin by melatonin

Tetrahydrobiopterin (BH4) is spontaneously released and extracellularly exe rts a toxic effect preferentially on catecholamine cells. Its synthesis rat e is mainly determined by the activity of the enzyme GTP cyclohydrolase I ( GTPCH). In the present study, role of melatonin in BH4 synthesis was determ ined using the catecholaminergic CATH.a cells. The neurohormone dose-depend ently reduced both intracellular and extracellular BH4 levels. This was due to both direct inhibition of catalytic activity of the existing GTPCH enzy me and down-regulation of GTPCH gene expression. Thus, melatonin is an effe ctive down-regulator of BH4 synthesis and is a potential therapeutic agent with which to control BH4 lever in aberrant conditions where it may rise to a toxic level. NeuroReport 11:3627-3630 (C) 2000 Lippincott Williams & Wil kins.