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Elimination of endogenous toxin, creatinine from blood plasma depends on albumin conformation: site specific uremic toxicity & impaired drug binding.

Varshney A, Rehan M, Subbarao N, Rabbani G, Khan RH - PLoS ONE (2011)

Bottom Line: Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination.The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding.These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.

ABSTRACT
Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

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Fluorescence quenching of HSA with creatinine at different ligand/protein ratios.Stern-Volmer (A&C) and modified Stern-Volmer (B&D) plots of N (A&B) and B (C&D) isomeric conformations of HSA with uremic toxin creatinine. Each data point was the mean of 3 independent observations (S.D. ranging 0.03–0.4%). The Protein was excited at 280 (♦) and 295 nm (◊).
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pone-0017230-g005: Fluorescence quenching of HSA with creatinine at different ligand/protein ratios.Stern-Volmer (A&C) and modified Stern-Volmer (B&D) plots of N (A&B) and B (C&D) isomeric conformations of HSA with uremic toxin creatinine. Each data point was the mean of 3 independent observations (S.D. ranging 0.03–0.4%). The Protein was excited at 280 (♦) and 295 nm (◊).

Mentions: Both the intensity and the position of the fluorescence emission spectrum of tryptophan were sensitive to changes in the fluorescence environment and consequently to the protein conformation. Hence, to understand the influence of creatinine binding on the neutral and basic form of HSA we studied the changes in the intrinsic fluorescence of the protein. Figure 5 shows the fluorescence spectra of HSA in the presence of increasing concentration of creatinine. The fluorescence quenching data were analyzed according to the Linear (Figure 5A and C) and modified Stern-Volmer equation (Figure 5B and D) [21], [35] after exciting the protein at 280 and 295 nm. We observed that, quenching of albumin fluorescence was not affecting the binding strength of tryptophan fluorescence. This may be so because binding of uremic toxin was not exactly at the site where tryptophan resides but it could be somewhere near to it as it mainly affects tyrosine fluorescence. These results are comparable with that of our ITC results and are presented in Table 2 further confirming that association constant Ka of uremic toxin depends on conformation of HSA underwent N-B transitions.


Elimination of endogenous toxin, creatinine from blood plasma depends on albumin conformation: site specific uremic toxicity & impaired drug binding.

Varshney A, Rehan M, Subbarao N, Rabbani G, Khan RH - PLoS ONE (2011)

Fluorescence quenching of HSA with creatinine at different ligand/protein ratios.Stern-Volmer (A&C) and modified Stern-Volmer (B&D) plots of N (A&B) and B (C&D) isomeric conformations of HSA with uremic toxin creatinine. Each data point was the mean of 3 independent observations (S.D. ranging 0.03–0.4%). The Protein was excited at 280 (♦) and 295 nm (◊).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3046181&req=5

pone-0017230-g005: Fluorescence quenching of HSA with creatinine at different ligand/protein ratios.Stern-Volmer (A&C) and modified Stern-Volmer (B&D) plots of N (A&B) and B (C&D) isomeric conformations of HSA with uremic toxin creatinine. Each data point was the mean of 3 independent observations (S.D. ranging 0.03–0.4%). The Protein was excited at 280 (♦) and 295 nm (◊).
Mentions: Both the intensity and the position of the fluorescence emission spectrum of tryptophan were sensitive to changes in the fluorescence environment and consequently to the protein conformation. Hence, to understand the influence of creatinine binding on the neutral and basic form of HSA we studied the changes in the intrinsic fluorescence of the protein. Figure 5 shows the fluorescence spectra of HSA in the presence of increasing concentration of creatinine. The fluorescence quenching data were analyzed according to the Linear (Figure 5A and C) and modified Stern-Volmer equation (Figure 5B and D) [21], [35] after exciting the protein at 280 and 295 nm. We observed that, quenching of albumin fluorescence was not affecting the binding strength of tryptophan fluorescence. This may be so because binding of uremic toxin was not exactly at the site where tryptophan resides but it could be somewhere near to it as it mainly affects tyrosine fluorescence. These results are comparable with that of our ITC results and are presented in Table 2 further confirming that association constant Ka of uremic toxin depends on conformation of HSA underwent N-B transitions.

Bottom Line: Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination.The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding.These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.

ABSTRACT
Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state.

Show MeSH
Related in: MedlinePlus