Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process.
In order to increase the tissue level of tetrahydrobiopterin (BH4), supplementation with 6R-tetrahydrobiopterin (6RBH4) has been widely employed. In this work, the effectiveness of 6RBH4 was compared with 7,8-dihydrobiopterin (7,8BH2) and sepiapterin by administration to mice. Administration of 6RBH4 was the least effective in elevating tissue BH4 levels in mice while sepiapterin was the best. In all three cases, a dihydrobiopterin surge appeared in the blood. The appearance of the dihydrobiopterin surge after BH4 treatment suggested that systemic oxidation of the administered BH4 had occurred before accumulation of BH4 in the tissues. This idea was supported by the following evidences: 1) An increase in tissue BH4 was effectively inhibited by methotrexate, an inhibitor of dihydrofolate reductase which reduces 7,8BH2 to BH4. 2) When the unnatural diastereomer 6SBH4 was administered to mice, a large proportion of the recovered BH4 was in the form of the 6R-diastereomer, suggesting that this BH4 was the product of a dihydrofolate reductase process by which 7,8BH2 converts to 6RBH4. These results indicated that the exogenous BH4 was oxidized and the resultant 7,8BH2 circulated through the tissues, and then it was incorporated by various other tissues and organs through a pathway shared by the exogenous sepiapterin and 7,8BH2 in their uptake. It was demonstrated that maintaining endogenous tetrahydrobiopterin in tissues under ordinary conditions was also largely dependent on an methotrexate-sensitive process, suggesting that cellular tetrahydrobiopterin was maintained both by de novo synthesis and by salvage of extracellular dihydrobiopterin.
Sawabe
Keiko
K
Department of Biosciences, Teikyo University of Science and Technology, Uenohara, Yamanashi 409-0193, Japan. k-sawabe@st.ntu.ac.jp
Wakasugi
Kazunori Osuke
KO
Hasegawa
Hiroyuki
H
D000818:Animals; D001708:Biopterins / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D005493:Folic Acid Antagonists; D001708:Biopterins; C017226:7,8-dihydrobiopterin; C003402:sapropterin