Abstract:
:(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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Anastasiadis PZ,States JC,Imerman BA,Louie MC,Kuhn DM,Levine RAsubject
Has Abstractpub_date
1996-01-01 00:00:00pages
149-55issue
1eissn
0026-895Xissn
1521-0111journal_volume
49pub_type
杂志文章abstract::Anthracyclines are potent anticancer agents, but their use is limited by cardiotoxicity at high cumulative doses. The mechanisms involved in anthracycline-mediated cardiotoxicity are still poorly understood, but numerous investigations have indicated a role for iron in this process. Our previous studies using neoplast...
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