Xanthine urolithiasis: Inhibitors of xanthine crystallization

PLoS One. 2018 Aug 29;13(8):e0198881. doi: 10.1371/journal.pone.0198881. eCollection 2018.


Objective: To identify in vitro inhibitors of xanthine crystallization that have potential for inhibiting the formation of xanthine crystals in urine and preventing the development of the renal calculi in patients with xanthinuria.

Methods: The formation of xanthine crystals in synthetic urine and the effects of 10 potential crystallization inhibitors were assessed using a kinetic turbidimetric system with a photometer. The maximum concentration tested for each compound was: 20 mg/L for 3-methylxanthine (3-MX); 40 mg/L for 7-methylxanthine (7-MX), 1-methylxanthine (1-MX), theobromine (TB), theophylline, paraxanthine, and caffeine; 45 mg/L for 1-methyluric acid; 80 mg/L for 1,3-dimethyluric acid; and 200 mg/L for hypoxanthine. Scanning electron microscopy was used to examine the morphology of the crystals formed when inhibitory effects were observed.

Results: Only 7-MX, 3-MX, and 1-MX significantly inhibited xanthine crystallization at the tested concentrations. Mixtures of inhibitors had an additive effect rather than a synergistic effect on crystallization.

Conclusion: Two of the inhibitors identified here-7-MX and 3-MX-are major metabolites of TB. In particular, after TB consumption, 20% is excreted in the urine as TB, 21.5% as 3-MX, and 36% as 7-MX. Thus, consumption of theobromine could protect patients with xanthinuria from the development of renal xanthine calculi. Clinical trials are necessary to demonstrate these effects in vivo.

MeSH terms

  • Aldehyde Oxidase / deficiency
  • Aldehyde Oxidase / urine
  • Chemical Precipitation / drug effects*
  • Crystallization
  • Down-Regulation / drug effects
  • Humans
  • In Vitro Techniques
  • Kidney Calculi / chemistry*
  • Kidney Calculi / prevention & control*
  • Metabolism, Inborn Errors / prevention & control
  • Metabolism, Inborn Errors / urine
  • Purine-Pyrimidine Metabolism, Inborn Errors / prevention & control
  • Purine-Pyrimidine Metabolism, Inborn Errors / urine
  • Urolithiasis* / prevention & control
  • Urolithiasis* / urine
  • Xanthine / antagonists & inhibitors
  • Xanthine / chemistry*
  • Xanthine / urine
  • Xanthine Dehydrogenase / deficiency
  • Xanthine Dehydrogenase / urine
  • Xanthines / pharmacology*


  • Xanthines
  • Xanthine
  • methylxanthine
  • 7-methylxanthine
  • Xanthine Dehydrogenase
  • Aldehyde Oxidase
  • 3-methylxanthine

Supplementary concepts

  • Xanthinuria, Type I
  • Xanthinuria, Type II

Grant support

The authors received no specific funding for this work.