title: Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model.
abstract: OBJECTIVE
  To assess the effectiveness of l-cystine dimethyl ester (CDME), an inhibitor of cystine crystal growth, for the treatment of cystine urolithiasis in an Slc3a1 knockout mouse model of cystinuria.
  
  
  METHODS
  CDME (200 μg per mouse) or water was delivered by gavage daily for 4 weeks. Higher doses by gavage or in the water supply were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical methods.
  
  
  RESULTS
  Treatment with CDME led to a significant decrease in stone size compared with that of the water group (P = .0002), but the number of stones was greater (P = .005). The change in stone size distribution between the 2 groups was evident by micro computed tomography. Overall, cystine excretion in urine was the same between the 2 groups (P = .23), indicating that CDME did not interfere with cystine metabolism. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit, with numerous small crystals. l-cysteine methyl ester was detected by ultra-performance liquid chromatography-mass spectrometer in stones from the CDME group only, indicating that a CDME metabolite was incorporated into the crystal structure. No pathologic changes were observed at the doses tested.
  
  
  CONCLUSIONS
  These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ. Electronic address: sahota@biology.rutgers.edu.
authors.forename: Amrik
authors.initials: A
authors.lastname: Sahota
authors.affiliation: Division of Urology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ.
authors.forename: Jaspreet S
authors.initials: JS
authors.lastname: Parihar
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Capaccione
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Noll
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ.
authors.forename: Derek
authors.initials: D
authors.lastname: Gordon
authors.affiliation: Laboratory Animal Services, Rutgers University, Piscataway, NJ.
authors.forename: David
authors.initials: D
authors.lastname: Reimer
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ.
authors.forename: Ill
authors.initials: I
authors.lastname: Yang
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Buckley
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ.
authors.forename: Marianne
authors.initials: M
authors.lastname: Polunas
authors.affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, New York University, New York, NY.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ward
authors.affiliation: Nephrology Division, New York University Langone Medical Center, New York, NY.
authors.forename: David S
authors.initials: DS
authors.lastname: Goldfarb
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, NJ.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D000818:Animals; D002853:Chromatography, Liquid; D003553:Cystine / Q000031:analogs & derivatives* / Q000737:chemistry; D003555:Cystinuria / Q000188:drug therapy* / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D052878:Urolithiasis / Q000188:drug therapy*; D055114:X-Ray Microtomography
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; C553309:L-cystine dimethylester; C489858:Slc3a1 protein, mouse; D003553:Cystine