Organic anion transporter 3
organic anion transmembrane transporter activity
Organic anion transporters, OAT1 and OAT3, are crucial biopterin transporters involved in bodily distribution of tetrahydrobiopterin and exclusion of its excess.
Tetrahydrobiopterin (BH<sub>4</sub>) is a common coenzyme of phenylalanine-, tyrosine-, and tryptophan hydroxylases, alkylglycerol monooxygenase, and NO synthases (NOS). Synthetic BH<sub>4</sub> is used medicinally for BH<sub>4</sub>-responsive phenylketonuria and inherited BH<sub>4</sub> deficiency. BH<sub>4</sub> 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<sub>2</sub>, the oxidized form of BH<sub>4</sub>. An increase in the BH<sub>2</sub>/BH<sub>4</sub> ratio leads to NOS dysfunction. Previous studies revealed that BH<sub>4</sub> supplementation caused a rapid urinary loss of BH<sub>4</sub> accompanied by an increase in the blood BH<sub>2</sub>/BH<sub>4</sub> 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<sub>4</sub> and/or BH<sub>2</sub>) 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<sub>2</sub> and sepiapterin as their substrate roughly 5- to 10-fold more than BH<sub>4</sub>. 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<sub>4</sub> and the exclusion to urine of a BH<sub>4</sub> excess, particularly when BH<sub>4</sub> was administered, and (3) in scavenging blood BH<sub>2</sub> by cellular uptake as the gateway to the salvage pathway of BH<sub>4</sub>, which reduces BH<sub>2</sub> back to BH<sub>4</sub>.