Abstract
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.
Highlights
Tetrahydrobiopterin (BH4) is an essential cofactor for a group of aromatic amino acid hydroxylases [1,2,3,4]
Urinary excretion was the major route of BP loss while bile was a minor route Renal exclusion of BH4 immediately after 6RBH4 administration was remarkably rapid
The tubular secretion of exogenously administered BH4 was effectively suppressed by prior administration of Pbc, as shown in this report, providing confirmative evidence supporting a previous observation using cyclosporin A (CsA) [12, 13]
Summary
Tetrahydrobiopterin (BH4) is an essential cofactor for a group of aromatic amino acid hydroxylases [1,2,3,4]. A guide for the therapeutic use of BH4 is available [5] This compound ameliorates hyperphenylalaninemia in cases of inherited BH4 deficiency [6, 7] and benefits patients with BH4-responsive phenylketonuria [8]. Once 6RBH4 is administered, it replaces innate BH4 and is integrated through endogenous metabolic pathways, similar to the intake of vitamins. We demonstrated that urinary excretion of administered 6RBH4 at a pharmacological dose predominantly involved secretion across renal tubular epithelium, distinct from glomerular filtration. We observed that the tubular secretion was almost completely suppressed by cyclosporin A (CsA), an inhibitor of transporters with broad specificity in excretion of xenobiotics and metabolic wastes. We revised the role of the salvage pathway of BH4 biosynthesis in scavenging BH2 in terms of its passage through the liver and kidney under the conditions of 6RBH4 administration
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