Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice
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.
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