Cyclosporin A-induced changes in endogenous metabolites in rat urine: a metabonomic investigation using high field NMR spectroscopy, HPLC-TOF/MS and chemometrics

Lenz, Eva M.; Bright, Jonathan; Knight, Richard; Wilson, Ian D.; Major, Hilary

doi:10.1016/j.jpba.2004.02.013

Cited by 133 publications

(80 citation statements)

References 19 publications

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“…4b), while TMA concentrations are not different with cyclosporine treatment as compared with controls. Lenz et al [31] treated rats with 45 mg/kg/day cyclosporine, which after 7 days resulted in increased urine concentrations of glucose, TMA and succinate. Some of these metabolite changes were also found in this study; however, we also noted major differences including succinate concentrations in urine that were significantly decreased in group 6 after 7 days.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Schmitz

Klawitter

Bendrick-Peart³

et al. 2009

Nephron Exp Nephrol

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Background: Cyclosporine and/or sirolimus impair recovery of renal transplants. This study examines the changes in urine metabolite profiles as surrogate markers of renal cell metabolism and function after cyclosporine and/or sirolimus treatment employing a rat kidney transplantation model. Methods: Using inbred Lewis rats, kidneys were transplanted into bilaterally nephrectomized recipients followed by treatment with either CsA (cyclosporine) 10, Rapa (sirolimus) 1, CsA10/Rapa1 or CsA25/Rapa1 mg/kg/day for 7 days. On day 7, urine was analyzed by ¹H-NMR spectroscopy. Blood and kidney tissue drug concentrations, tissue high-energy compounds (including ATP, ADP) and oxidative stress markers (15-F_2t-isoprostanes) in urine were measured by HPLC mass spectrometry. Results: Changes in urine metabolites followed the order Rapa1 < CsA10 < CsA10/Rapa1 < CsA25/Rapa1. Compared with controls, CsA25/Rapa1 showed the greatest changes (creatinine –36%, succinate –57%, citrate –89%, α-ketoglutarate –75%, creatine +498%, trimethylamine +210% and taurine +370%). 15-F_2t-isoprostane concentrations in urine increased in the combined immunosuppressant-treated animals ([CsA25/Rapa1]: 795 ± 222, [CsA10/Rapa1]: 475 ± 233 pg/mg/creatinine) as compared with controls (165 ± 78 pg/mg creatinine). Rapa concentration in blood and tissues increased in the combined treatment (blood: 31 ± 8 ng/ml, tissue: 1.3 ± 0.4 ng/mg) as compared with monotherapy (blood: 14 ± 8 ng/ml, tissue: 0.35 ± 0.15 ng/mg). Drug blood concentrations correlated with isoprostane urine concentrations, which correlated negatively with citrate, α-ketoglutarate and creatinine concentrations in urine. Only CsA25/Rapa1 significantly reduced high-energy metabolite concentrations in transplant kidney tissue (ATP –55%, ADP –24%). Conclusion: Immunosuppressant drugs induce changes in urine metabolite patterns, suggesting that immunosuppressant-induced oxidative stress is an early event in the development of nephrotoxicity. Urine 15-F_2t-isoprostane concentrations and metabolite profiles may be sensitive markers of immunosuppressant-induced nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Schmitz

Klawitter

Bendrick-Peart³

et al. 2009

Nephron Exp Nephrol

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“…Again application of all three platforms should be the best and safest resort for more comprehensive metabolome coverage, better validation of results, or unambiguous marker identification. Efforts are needed to work in parallel or to combine these complex data sets (see, for example, GC-MS and LC-MS data combination in Sreekumar et al, 2009;t'Kindt et al, 2009;Gao et al, 2008; NMR and LC-MS data combinations in Lenz et al, 2004b;Law et al, 2009) and to develop tools to assist data mining.…”

Section: Discussionmentioning

confidence: 99%

Mass spectrometry‐based holistic analytical approaches for metabolite profiling in systems biology studies

Theodoridis

Gika

Wilson

2011

Mass Spectrometry Reviews

189

125

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Metabonomics and metabolomics represent one of the three major platforms in systems biology. To perform metabolomics it is necessary to generate comprehensive "global" metabolite profiles from complex samples, for example, biological fluids or tissue extracts. Analytical technologies based on mass spectrometry (MS), and in particular on liquid chromatography-MS (LC-MS), have become a major tool providing a significant source of global metabolite profiling data. In the present review we describe and compare the utility of the different analytical strategies and technologies used for MS-based metabolomics with a particular focus on LC-MS. Both the advantages offered by the technology and also the challenges and limitations that need to be addressed for the successful application of LC-MS in metabolite analysis are described. Data treatment and approaches resulting in the detection and identification of biomarkers are considered. Special emphasis is given to validation issues, instrument stability, and QA/quality control (QC) procedures.

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“…Reference was also made to the library and peak fitting routine contained within the Chenomx software and the previous literature (Bollard et al, 2001;Connor et al, 2004;Griffin et al, 2000;Lenz et al, 2004). The online Madison Metabolomics Consortium Database (http://mmcd.nmrfam.wisc.edu/index.html) was also consulted.…”

Section: H-nmr Analysismentioning

confidence: 99%

Comparisons of metabolic and physiological changes in rats following short term oral dosing with pesticides commonly found in food

Jones

Murfitt

Svendsen

et al. 2013

Food and Chemical Toxicology

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Contact CEH NORA team at noraceh@ceh.ac.ukThe NERC and CEH trademarks and logos ('the Trademarks') are registered trademarks of NERC in the UK and other countries, and may not be used without the prior written consent of the Trademark owner. male Fischer F344 rats in order to assess the metabolic changes induced by oral exposure to two benzimidazole fungicides (carbendazim and thiabendazole) and two bipyridyllium herbicides (chlormequat and mepiquat). Exposure levels were selected to be lower than those expected to cause overt signs of toxicity. We then compared the sensitivity of the metabolomics approach to more traditional methods of toxicity assessment such as the measurement of growth and organ weights. Separate, acute exposure experiments were conducted for each pesticide to identify potential metabolic markers of exposure across four doses (and a control). Growth, organ weights and feeding/drinking rates were not significantly affected by any compounds at any dose levels tested. In contrast, metabolic responses were detected within 8 and 24 hours for chlormequat and mepiquat, and after 24 hours for carbendazim and thiabendazole. These results demonstrate the potential for the use of metabolomics in food toxicity testing.

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Cyclosporin A-induced changes in endogenous metabolites in rat urine: a metabonomic investigation using high field NMR spectroscopy, HPLC-TOF/MS and chemometrics

Cited by 133 publications

References 19 publications

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Metabolic Profiles in Urine Reflect Nephrotoxicity of Sirolimus and Cyclosporine following Rat Kidney Transplantation

Mass spectrometry‐based holistic analytical approaches for metabolite profiling in systems biology studies

Comparisons of metabolic and physiological changes in rats following short term oral dosing with pesticides commonly found in food

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