Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice
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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.
- Kwon N.S., Nathan C.F., Stuehr D.J.: Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem 264: 20496–20501, 1989.
- Mayer B., John M, Heinzel B., Werner E.R., Wächter H., Schultz G., Bohme E. Brain nitric oxide synthase is a biopterin- and flavin-containing multi-functional oxido-reductase. FEBS Lett 288: 187–191, 1991. CrossRef
- Kaufman S. The structure of the phenylalanine hydroxylation cofactor. Proc Natl Acad Sci USA 50: 1085–1093, 1963. CrossRef
- Nagatsu T., Levitt M., Udenfriend S. Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem 239: 2910–2917, 1964.
- Lovenberg W., Jequier E., Sjoerdsma A. Tryptophan hydroxylation: measurement in pineal gland, brainstem, and carcinoid tumor. Science 155: 217–219, 1967. CrossRef
- Ichiyama A., Nakamura S., Nishizuka Y., Hayashi O. Enzymic studies on the biotynthesis of serotonin in mammalian brain J Biol Chem 245: 1699–1709, 1970.
- Yamamoto K., Nagano M., Kakanishi N., Hasegawa H. A comparison of sepiapterin and tetrahydrobiopterin uptake by RBL2H3 cells. Pteridines 7: 154–156, 1996.
- Yamamoto K., Nakazawa N., Hasegawa H., Nakanishi N., “Uptake of tetrahydrobiopterin by tells in monolayer cultures of RBL2H3 and PC 12 cell line.” In Cemistry and Biology of Pteridines and Folates 1997, W. Pfleiderer, H. Rocos, eds, Blackwell Science, Berlin, pp 759–763, 1997.
- Hasegawa H., Oguro K., Naito Y., Ichiyama A. Iron dependence of tryptophan hydroxylase activity in RBL2H3 cells and its manipulation by chelators. Eur J Biochem 261:734–739, 1999. CrossRef
- Fukushima T., Nixon J.C. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem 102: 176–188, 1980. CrossRef
- Kobayashi T., Hasegawa H., Kaneko E., Ichiyama A. Gastrointestinal serotonin: Depletion due to tetrahydrobiopterin deficiency induced by 2,4-diamino-6-hydroxypyrimidine administration. J Pharmacol Exp Ther. 256: 773–779, 1990.
- Hasegawa H., Yamamoto K., Matsuhashi Y., Miyazawa T., Nakanishi N. Ability of RBL2H3 cells to lower environmental Ttetrahydrobiopterin concentratioa. Pteridines 11: 121–125, 2000.
- Hasegawa H., Yamamoto K., Sawabe K., Matsuhashi Y., Oguro K., Nakanishi N. Cells take up BH4, oxidized it and the oxidized biopterin is preferentially released. Proceedings of the 12th International Symposium on the Chemistry and Biology of Pteridines and Folates, Milstien, S., Kapatos, G., Shane, B., Levine, R.A., eds, Kluwer Academic Press, this volume
- Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice
- Book Title
- Chemistry and Biology of Pteridines and Folates
- Book Subtitle
- Proceedings of the 12th International Symposium on Pteridines and Folates, National Institutes of Health, Bethesda, Maryland, June 17–22, 2001
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- pp 199-204
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- Springer Science+Business Media New York
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- Author Affiliations
- 1. Department of Biosciences, Teikyo University of Science and Technology, Uenohara, Yamanashi, Japan, 409-0193
- 2. Department of Biotechnology Research Center, Teikyo University of Science and Technology, Uenohara, Yamanashi, 409-0193, Japan
- 3. Internal Medicine Clinical Immunohaematology, Hachioji, Japan
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