期刊
JOURNAL OF PHARMACOLOGICAL SCIENCES
卷 96, 期 2, 页码 124-133出版社
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.FP0040280
关键词
dihydrofolate reductase; tetrahydrobiopterin; sepiapterin; methotrexate
In order to increase the tissue level of tetrahydrobiopterin (BH4), supplementation with 6R-tetrahydroblopterin (6R-BH4) has been widely employed. In this work, the effectiveness of 6RBH(4) was compared with 7,8-dihydrobiopterin (7,8BH(2)) and sepiapterin by administration to mice. Administration of 6RBH(4) 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 7,8BH(2) to BH4. 2) When the unnatural diastereomer 6SBH(4) 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 7,8BH(2) converts to 6RBH(4). These results indicated that the exogenous BH4 was oxidized and the resultant 7,8BH(2) circulated through the tissues, and then it was incorporated by various other tissues and organs through a pathway shared by the exogenous sepiapterin and 7,8BH(2) 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据