Organic anion transporters, OAT1 and OAT3, are crucial biopterin transporters involved in bodily distribution of tetrahydrobiopterin and exclusion of its excess.

Tetrahydrobiopterin (BH₄) is a common coenzyme of phenylalanine-, tyrosine-, and tryptophan hydroxylases, alkylglycerol monooxygenase, and NO synthases (NOS). Synthetic BH₄ is used medicinally for BH₄-responsive phenylketonuria and inherited BH₄ deficiency. BH₄ supplementation has also drawn attention as a therapy for various NOS-related cardio-vascular diseases, but its use has met with limited success in decreasing BH₂, the oxidized form of BH₄. An increase in the BH₂/BH₄ ratio leads to NOS dysfunction. Previous studies revealed that BH₄ supplementation caused a rapid urinary loss of BH₄ accompanied by an increase in the blood BH₂/BH₄ ratio and an involvement of probenecid-sensitive but unknown transporters was strongly suggested in these processes. Here we show that OAT1 and OAT3 enabled cells to take up BP (BH₄ and/or BH₂) in a probenecid-sensitive manner using rat kidney slices and transporter-expressing cell systems, LLC-PK1 cells and Xenopus oocytes. Both OAT1 and OAT3 preferred BH₂ and sepiapterin as their substrate roughly 5- to 10-fold more than BH₄. Administration of probenecid acutely reduced the urinary exclusion of endogenous BP accompanied by a rise in blood BP in vivo. These results indicated that OAT1 and OAT3 played crucial roles: (1) in determining baseline levels of blood BP by excluding endogenous BP through the urine, (2) in the rapid distribution to organs of exogenous BH₄ and the exclusion to urine of a BH₄ excess, particularly when BH₄ was administered, and (3) in scavenging blood BH₂ by cellular uptake as the gateway to the salvage pathway of BH₄, which reduces BH₂ back to BH₄.

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