Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice
Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice
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与正常小鼠中补充 BH4 相比，使用墨蝶呤可以更有效地提高组织 BH4 水平
DOI：
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
H. Hasegawa
中科院分区：
文献类型：
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作者：
K. Sawabe;Kazumasa Yamamoto;T. Kamata;O. Wakasugi;H. Hasegawa
四氢生物蝶呤（BH 4）是一氧化氮合成酶（1，2）以及苯丙氨酸（3）、酪氨酸（4）和色氨酸（5，6）的芳香族氨基酸羟化酶的重要辅因子。BH 4补充剂已被有效地用于治疗许多由BH 4缺乏引起的神经元功能障碍的病例。各种与生活方式相关的疾病，如糖尿病和高血压，都与NO合成障碍有关，因此它们是补充BH 4的潜在目标。因此，BH 4补充剂将在未来越来越多的病例中使用。然而，众所周知，口服给予的BH 4不能非常有效地被吸收。在我们使用培养的RBL 2 H3和PC-12细胞的体外工作中，显示BH 4的摄取受到某些细胞功能的阻碍，以排除它，导致非常低效的掺入（7），而sepiapterin（SP），通过补救途径合成BH 4的前体，被掺入并非常有效地转化为BH 4（8）。此外，从外源SP新“合成”的BH 4在其周转率和作为辅因子支持高色氨酸羟化酶活性的能力方面与内源BH 4没有区别（9）。基于这些观察结果，我们寻找一种有效的方法来增加正常小鼠组织中的BH 4水平。在这项工作中，我们观察到SP被小鼠有效地摄取，并且各种组织中的BH 4水平比6 RBH 4给药引起的水平增加得更多并且持续时间更长。
Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthetase (1, 2) as well as of aromatic amino acid hydroxylases of phenylalanine (3), tyrosine (4), and tryptophan (5, 6). BH4-supplement has been used effectively to treat many cases of neuronal dysfunctions caused by BH4 deficiency. Various life style-related diseases such as diabetes and hypertension are related to disorders in NO-synthesis and therefore they are potential targets for BH4-supplementation. Hence, BH4-supplements will be used in increasing numbers of these cases in the future. However, it is well known that BH4 administered orally is not taken up very efficiently. In our in vitro work using cultured RBL2H3 and PC-12 cells, uptake of BH4 was shown to be hampered by some cellular function to exclude it resulting in very inefficient incorporation (7), while sepiapterin (SP), a precursor of BH4 synthesis through the salvage pathway, was incorporated and converted to BH4 very efficiently (8). Further, the newly “synthesized” BH4 from exogenous SP was indistinguishable from endogenous BH4 in terms of its turnover rate and ability to support high tryptophan hydroxylase activity as a cofactor (9). Based on these observations, we searched for an effective method to increase tissue BH4 levels in normal mice. In this work, we observed that SP was efficiently taken up by mice and BH4 levels in various tissues increased much more and lasted longer than those resulting from 6RBH4 administration.
DOI：
10.1016/s0021-9258(19)47089-0
发表时间：
1989-12
期刊：
The Journal of biological chemistry
影响因子：
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作者：
N. Kwon;C. Nathan;D. Stuehr
通讯作者：
N. Kwon;C. Nathan;D. Stuehr