PT  - JOURNAL ARTICLE
AU  - P Z Anastasiadis
AU  - J C States
AU  - B A Imerman
AU  - M C Louie
AU  - D M Kuhn
AU  - R A Levine
TI  - Mitogenic effects of tetrahydrobiopterin in PC12 cells.
DP  - 1996 Jan 01
TA  - Molecular Pharmacology
PG  - 149--155
VI  - 49
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/49/1/149.short
4100  - http://molpharm.aspetjournals.org/content/49/1/149.full
SO  - Mol Pharmacol1996 Jan 01; 49
AB  - (6R)-5,6,7,8-Tetrahydrobiopterin (BH4), which is synthesized intracellularly from GTP, caused a concentration-dependent increase in rat pheochromocytoma (PC12) cell proliferation when added exogenously. Incubation with sepiapterin, which is converted enzymatically to BH4 within cells, also increased PC12 cell proliferation and BH4 levels concomitantly. These sepiapterin effects were mediated by BH4 as inhibition of sepiapterin conversion to BH4 by a sepiapterin reductase inhibitor, N-acetyl-serotonin, blocked the increase in proliferation and the elevation of BH4 levels. 7,8-Dihydrobiopterin (BH2) also increased BH4 levels and PC12 cell proliferation, both of which were reversed by methotrexate, which blocks the conversion of BH2 to BH4 by dihydrofolate reductase. The BH4-induced increase in PC12 cell proliferation was not related to elevated catecholamine or nitric oxide synthesis as inhibitors of tyrosine hydroxylase or nitric oxide synthase did not reduce the BH4 effect. BH4 and its precursors did not alter intracellular cAMP levels, suggesting that this second messenger is not involved in the enhancement of PC12 cell proliferation by BH4. Sepiapterin and BH4 also enhanced the proliferation of SV40-transformed human fibroblasts and rat C6 glioma cells, indicating that the stimulatory effect of BH4 on cell proliferation is not restricted to PC12 cells.