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Tetrahydrobiopterin (BH 4 ) is a common coenzyme of phenylalanine-, tyrosine-, and tryptophan hydroxylases, alkylglycerol monooxygenase, and NO synthases (NOS). Synthetic BH 4 is used medicinally for BH 4 -responsive phenylketonuria and inherited BH 4 deficiency. BH 4 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 BH 2 , the oxidized form of BH 4 . An increase in the BH 2 /BH 4 ratio leads to NOS dysfunction. Previous studies revealed that BH 4 supplementation caused a rapid urinary loss of BH 4 accompanied by an increase in the blood BH 2 /BH 4 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 (BH 4 and/or BH 2 ) 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 BH 2 and sepiapterin as their substrate roughly 5- to 10-fold more than BH 4 . 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 BH 4 and the exclusion to urine of a BH 4 excess, particularly when BH 4 was administered, and (3) in scavenging blood BH 2 by cellular uptake as the gateway to the salvage pathway of BH 4 , which reduces BH 2 back to BH 4 .

molecular and cellular biochemistry

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