Anastasiadis P Z, States J C, Imerman B A, Louie M C, Kuhn D M, Levine R A
Gossett Neurology Laboratories, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Mol Pharmacol. 1996 Jan;49(1):149-55.
(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.
(6R)-5,6,7,8-四氢生物蝶呤（BH4）由鸟苷三磷酸在细胞内合成，外源性添加时可引起大鼠嗜铬细胞瘤（PC12）细胞增殖呈浓度依赖性增加。与在细胞内可酶促转化为BH4的蝶酰三谷氨酸共同孵育，也可同时增加PC12细胞增殖和BH4水平。这些蝶酰三谷氨酸的作用是由BH4介导的，因为蝶酰三谷氨酸还原酶抑制剂N-乙酰血清素抑制蝶酰三谷氨酸向BH4的转化，从而阻断了增殖增加和BH4水平升高。7,8-二氢生物蝶呤（BH2）也增加了BH4水平和PC12细胞增殖，二者均被甲氨蝶呤逆转，甲氨蝶呤可通过二氢叶酸还原酶阻断BH2向BH4的转化。BH4诱导的PC12细胞增殖增加与儿茶酚胺或一氧化氮合成增加无关，因为酪氨酸羟化酶或一氧化氮合酶抑制剂并未降低BH4的作用。BH4及其前体未改变细胞内cAMP水平，提示该第二信使不参与BH4对PC12细胞增殖的增强作用。蝶酰三谷氨酸和BH4也增强了SV40转化的人成纤维细胞和大鼠C6胶质瘤细胞的增殖，表明BH4对细胞增殖的刺激作用并不局限于PC12细胞。
