Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model

Amrik Sahota, Jaspreet S. Parihar, Kathleen M. Capaccione, Min Yang, Kelsey Noll, Derek Gordon, David Reimer, Ill Yang, Brian T. Buckley, Marianne Polunas, Kenneth R. Reuhl, Matthew R. Lewis, Michael Ward, David S. Goldfarb, Jay A. Tischfield

Research output: Contribution to journalArticle

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.

Materials and 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.

Conclusion 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.

Original languageEnglish (US)
Pages (from-to)1249.e9-1249.e15
JournalUrology
Volume84
Issue number5
DOIs
StatePublished - Nov 1 2014

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Cystinuria
Urolithiasis
Cystine
Knockout Mice
Esters
Crystallization
cystine dimethyl ester
Water
Water Supply
Liquid Chromatography
Electron Scanning Microscopy
Habits
Tomography

ASJC Scopus subject areas

  • Urology

Cite this

Sahota, A., Parihar, J. S., Capaccione, K. M., Yang, M., Noll, K., Gordon, D., ... Tischfield, J. A. (2014). Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. Urology, 84(5), 1249.e9-1249.e15. https://doi.org/10.1016/j.urology.2014.07.043

Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. / Sahota, Amrik; Parihar, Jaspreet S.; Capaccione, Kathleen M.; Yang, Min; Noll, Kelsey; Gordon, Derek; Reimer, David; Yang, Ill; Buckley, Brian T.; Polunas, Marianne; Reuhl, Kenneth R.; Lewis, Matthew R.; Ward, Michael; Goldfarb, David S.; Tischfield, Jay A.

In: Urology, Vol. 84, No. 5, 01.11.2014, p. 1249.e9-1249.e15.

Research output: Contribution to journalArticle

Sahota, A, Parihar, JS, Capaccione, KM, Yang, M, Noll, K, Gordon, D, Reimer, D, Yang, I, Buckley, BT, Polunas, M, Reuhl, KR, Lewis, MR, Ward, M, Goldfarb, DS & Tischfield, JA 2014, 'Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model', Urology, vol. 84, no. 5, pp. 1249.e9-1249.e15. https://doi.org/10.1016/j.urology.2014.07.043
Sahota A, Parihar JS, Capaccione KM, Yang M, Noll K, Gordon D et al. Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. Urology. 2014 Nov 1;84(5):1249.e9-1249.e15. https://doi.org/10.1016/j.urology.2014.07.043
Sahota, Amrik ; Parihar, Jaspreet S. ; Capaccione, Kathleen M. ; Yang, Min ; Noll, Kelsey ; Gordon, Derek ; Reimer, David ; Yang, Ill ; Buckley, Brian T. ; Polunas, Marianne ; Reuhl, Kenneth R. ; Lewis, Matthew R. ; Ward, Michael ; Goldfarb, David S. ; Tischfield, Jay A. / Novel cystine ester mimics for the treatment of cystinuria-induced urolithiasis in a knockout mouse model. In: Urology. 2014 ; Vol. 84, No. 5. pp. 1249.e9-1249.e15.
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AU - Parihar, Jaspreet S.

AU - Capaccione, Kathleen M.

AU - Yang, Min

AU - Noll, Kelsey

AU - Gordon, Derek

AU - Reimer, David

AU - Yang, Ill

AU - Buckley, Brian T.

AU - Polunas, Marianne

AU - Reuhl, Kenneth R.

AU - Lewis, Matthew R.

AU - Ward, Michael

AU - Goldfarb, David S.

AU - Tischfield, Jay A.

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N2 - 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.Materials and 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.Conclusion 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.

AB - 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.Materials and 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.Conclusion 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.

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