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

Mol Cell Biochem. 2017 Nov;435(1-2):97-108. doi: 10.1007/s11010-017-3060-7. Epub 2017 May 22.

Abstract

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.

Keywords: Biopterin transport; Dihydrobiopterin; Equilibrative nucleoside transporter; NOS dysfunction; Organic anion transporter; Tetrahydrobiopterin.

MeSH terms

  • Animals
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / physiology
  • Biopterin / analogs & derivatives*
  • Biopterin / genetics
  • Biopterin / metabolism
  • Cell Line
  • Oocytes
  • Organic Anion Transport Protein 1 / genetics
  • Organic Anion Transport Protein 1 / metabolism*
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Probenecid / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Xenopus

Substances

  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Slc22a6 protein, rat
  • organic anion transport protein 3
  • Biopterin
  • sapropterin
  • Probenecid