Theobromine inhibits uric acid crystallization. A potential application in the treatment of uric acid nephrolithiasis

PLoS One. 2014 Oct 21;9(10):e111184. doi: 10.1371/journal.pone.0111184. eCollection 2014.


Purpose: To assess the capacity of methylxanthines (caffeine, theophylline, theobromine and paraxanthine) to inhibit uric acid crystallization, and to evaluate their potential application in the treatment of uric acid nephrolithiasis.

Materials and methods: The ability of methylxathines to inhibit uric acid nucleation was assayed turbidimetrically. Crystal morphology and its modification due to the effect of theobromine were evaluated by scanning electron microscopy (SEM). The ability of theobromine to inhibit uric acid crystal growth on calculi fragments resulting from extracorporeal shock wave lithotripsy (ESWL) was evaluated using a flow system.

Results: The turbidimetric assay showed that among the studied methylxanthines, theobromine could markedly inhibit uric acid nucleation. SEM images showed that the presence of theobromine resulted in thinner uric acid crystals. Furthermore, in a flow system theobromine blocked the regrowth of post-ESWL uric acid calculi fragments.

Conclusions: Theobromine, a natural dimethylxanthine present in high amounts in cocoa, acts as an inhibitor of nucleation and crystal growth of uric acid. Therefore, theobromine may be clinically useful in the treatment of uric acid nephrolithiasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caffeine / chemistry
  • Caffeine / pharmacology
  • Crystallization*
  • Humans
  • Microscopy, Electron, Scanning
  • Nephrolithiasis / drug therapy*
  • Nephrolithiasis / metabolism
  • Oxalates / chemistry
  • Theobromine / chemistry
  • Theobromine / pharmacology*
  • Uric Acid / chemistry*


  • Oxalates
  • Uric Acid
  • Caffeine
  • Theobromine

Grant support

This work was supported by project grants CTQ2010-18271/PPQ and TEC2010-19467 from the Ministerio de Ciencia e Innovación (Gobierno de España), FEDER funds (European Union) and project grant 9/2011 from the Conselleria d'Educació, Cultura i Universitat (Govern de les Illes Balears). A.R. is grateful to the European Social Fund and the Conselleria d'Educació, Cultura i Universitats for the fellowship FPI/1570/2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.