Pii: S0304-3940(02)00497-4

Tetrahydrobiopterin (BH4) has a trophic effect on pheochromocytoma-12 (PC12) cells such as insulin-like growth factor-1 (IGF-1). We investigated involvement of BH4 in the trophic effect of IGF-1 on PC12 cells. IGF-1 (10–300 ng/ml) increased cellular BH4 content in a dose-related manner. Cellular BH4 content increased after 6–36 h incubation with IGF-1. IGF-1induced increase in the cellular BH4 content was blunted by 0.3 mM 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor for BH4 synthesis. IGF-1 protected PC12 cells from the cell death induced by depletion of serum and nerve growth factor, which was attenuated by DAHP. The effects of IGF-1 on the cellular BH4 content and cell viability were eliminated by 0.2mM wortmannin. These results suggest that BH4 is involved in the trophic effect of IGF-1 on PC12 cells and that the effect of IGF1 on BH4 synthesis is mediated by phosphatidylinositol 3-kinase. q 2002 Elsevier Science Ireland Ltd. All rights reserved.