Tetrahydrobiopterin Supplementation: Elevation of Tissue Biopterin Levels Accompanied by a Relative Increase in Dihydrobiopterin in the Blood and the Role of Probenecid-Sensitive Uptake in Scavenging Dihydrobiopterin in the Liver and Kidney of Rats.
Tetrahydrobiopterin Supplementation: Elevation of Tissue Biopterin Levels Accompanied by a Relative Increase in Dihydrobiopterin in the Blood and the Role of Probenecid-Sensitive Uptake in Scavenging Dihydrobiopterin in the Liver and Kidney of Rats.
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DOI：
10.1371/journal.pone.0164305
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hasegawa H
中科院分区：
文献类型：
--
作者：
Ohashi A;Saeki Y;Harada T;Naito M;Takahashi T;Aizawa S;Hasegawa H
四氢生物蝶呤（BH 4）是一氧化氮合酶（NOS）和芳香族氨基酸羟化酶的重要辅因子。BH 4和7，8-二氢生物蝶呤（BH 2）在代谢上可互换，但需要消耗NADPH。外源性BH 4可以被身体代谢，类似于维生素。目前，合成BH 4被用作孤儿药，用于需要BH 4补充的遗传性疾病患者。补充BH 4作为治疗某些心血管症状的手段也引起了人们的关注，然而，其在人类患者中的应用仍然有限。在此，我们追踪了BH 4给药（5 mg/kg大鼠，i. v.）后生物蝶呤（BP）在血液、胆汁、尿液、肝脏、肾脏和脑中的分布。预先用丙磺舒治疗或不用丙磺舒治疗，丙磺舒是摄取转运蛋白的有效抑制剂，特别是包括有机阴离子转运蛋白家族如OTA 1和OAT 3。BP在尿液中的快速排泄是由血液浓度升高驱动的，其消除在120分钟内达到约90%。在非常早期，BP被肝脏和肾脏吸收，并逐渐释放回血液。BH 4给药引起血液BP中BH4%的显著降低，这是一个不可避免的代偿过程。丙磺舒治疗减缓了血压的下降，同时抑制了其在肾脏中的初始快速排泄。同时，BH4%进一步降低，表明丙磺舒敏感的BP摄取在体内BH 2清除中起着至关重要的作用。这表明过量产生的BH 2通过丙磺舒敏感过程被器官吸收，然后通过BH 4补救途径逆转化为BH 4而被清除。综上所述，BH 4给药在几个小时内有效地提高了器官中的BP水平，但效率极低。由于相对于BH 4的高BH 2引起NOS功能障碍，因此在实践中必须避免BH4%的降低，否则将破坏补充剂改善NOS功能障碍的期望效果。
Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS) and aromatic amino acid hydroxylases. BH4 and 7,8-dihydrobiopterin (BH2) are metabolically interchangeable at the expense of NADPH. Exogenously administered BH4 can be metabolized by the body, similar to vitamins. At present, synthetic BH4 is used as an orphan drug for patients with inherited diseases requiring BH4 supplementation. BH4 supplementation has also drawn attention as a means of treating certain cardiovascular symptoms, however, its application in human patients remains limited. Here, we tracked biopterin (BP) distribution in blood, bile, urine, liver, kidney and brain after BH4 administration (5 mg/kg rat, i.v.) with or without prior treatment with probenecid, a potent inhibitor of uptake transporters particularly including organic anion transporter families such as OTA1 and OAT3. The rapid excretion of BP in urine was driven by elevated blood concentrations and its elimination reached about 90% within 120 min. In the very early period, BP was taken up by the liver and kidney and gradually released back to the blood. BH4 administration caused a considerable decrease in the BH4% in blood BP as an inevitable compensatory process. Probenecid treatment slowed down the decrease in blood BP and simultaneously inhibited its initial rapid excretion in the kidney. At the same time, the BH4% was further lowered, suggesting that the probenecid-sensitive BP uptake played a crucial role in BH2 scavenging in vivo. This suggested that the overproduced BH2 was taken up by organs by means of the probenecid-sensitive process, and was then scavenged by counter-conversion to BH4 via the BH4 salvage pathway. Taken together, BH4 administration was effective at raising BP levels in organs over the course of hours but with extremely low efficiency. Since a high BH2 relative to BH4 causes NOS dysfunction, the lowering of the BH4% must be avoided in practice, otherwise the desired effect of the supplementation in ameliorating NOS dysfunction would be spoiled.
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影响因子：
3.9
作者：
MIWA, S;WATANABE, Y;HAYAISHI, O
通讯作者：
HAYAISHI, O
影响因子：
37.8
作者：
COSENTINO, F;KATUSIC, ZS
通讯作者：
KATUSIC, ZS
影响因子：
3.8
作者：
Hasegawa, H;Sawabe, K;Wakasugi, OK
通讯作者：
Wakasugi, OK
DOI：
10.1073/pnas.50.6.1085
发表时间：
1963-01-01
影响因子：
11.1
作者：
KAUFMAN, S
通讯作者：
KAUFMAN, S
影响因子：
3.8
作者：
Ohashi, Akiko;Mamada, Kaori;Hasegawa, Hiroyuki
通讯作者：
Hasegawa, Hiroyuki