Renal Reabsorptive Transport of Uric Acid Precursor Xanthine by URAT1 and GLUT9

Biol Pharm Bull. 2020;43(11):1792-1798. doi: 10.1248/bpb.b20-00597.

Abstract

Xanthine and hypoxanthine are intermediate metabolites of uric acid and a source of reactive oxidative species (ROS) by xanthine oxidoreductase (XOR), suggesting that facilitating their elimination is beneficial. Since they are reabsorbed in renal proximal tubules, we investigated their reabsorption mechanism by focusing on the renal uric acid transporters URAT1 and GLUT9, and examined the effect of clinically used URAT1 inhibitor on their renal clearance when their plasma concentration is increased by XOR inhibitor. Uptake study for [3H]xanthine and [3H]hypoxanthine was performed using URAT1- and GLUT9-expressing Xenopus oocytes. Transcellular transport study for [3H]xanthine was carried out using Madin-Darby canine kidney (MDCK)II cells co-expressing URAT1 and GLUT9. In in vivo pharmacokinetic study, renal clearance of xanthine was estimated based on plasma concentration and urinary recovery. Uptake by URAT1- and GLUT9-expressing oocytes demonstrated that xanthine is a substrate of URAT1 and GLUT9, while hypoxanthine is not. Transcellular transport of xanthine in MDCKII cells co-expressing URAT1 and GLUT9 was significantly higher than those in mock cells and cells expressing URAT1 or GLUT9 alone. Furthermore, dotinurad, a URAT1 inhibitor, increased renal clearance of xanthine in rats treated with topiroxostat to inhibit XOR. It was suggested that xanthine is reabsorbed in the same manner as uric acid through URAT1 and GLUT9, while hypoxanthine is not. Accordingly, it is expected that treatment with XOR and URAT1 inhibitors will effectively decrease purine pools in the body and prevent cell injury due to ROS generated during XOR-mediated reactions.

Keywords: kidney; uric acid; uric acid reabsorptive transporter; xanthine; xanthine oxidoreductase.

MeSH terms

  • Animals
  • Anion Transport Proteins / antagonists & inhibitors
  • Anion Transport Proteins / metabolism*
  • Benzothiazoles / administration & dosage
  • Dogs
  • Glucose Transport Proteins, Facilitative / genetics
  • Glucose Transport Proteins, Facilitative / metabolism*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Madin Darby Canine Kidney Cells
  • Models, Animal
  • Monosaccharide Transport Proteins / metabolism*
  • Nitriles / administration & dosage
  • Oocytes
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism*
  • Pyridines / administration & dosage
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Renal Elimination / drug effects
  • Uric Acid / metabolism
  • Xanthine / blood
  • Xanthine / metabolism
  • Xanthine / pharmacokinetics*
  • Xanthine / urine
  • Xanthine Dehydrogenase / antagonists & inhibitors
  • Xanthine Dehydrogenase / metabolism
  • Xenopus laevis

Substances

  • Anion Transport Proteins
  • Benzothiazoles
  • GLUT6 protein, rat
  • Glucose Transport Proteins, Facilitative
  • Monosaccharide Transport Proteins
  • Nitriles
  • Organic Anion Transporters
  • Organic Cation Transport Proteins
  • Pyridines
  • Reactive Oxygen Species
  • Recombinant Proteins
  • SLC22A12 protein, human
  • SLC2A9 protein, human
  • Slc22a12 protein, rat
  • FYX-051
  • Xanthine
  • Uric Acid
  • dotinurad
  • Xanthine Dehydrogenase