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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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Related in: MedlinePlus

Displacing effect of HSA site specific markers on the ICD signal of creatinine-HSA complex.Results of CD displacement experiments performed with warfarin, phenylbutazone, ibuprofen and diazepam on HSA-CTN complex at (A) pH 7.0 and (B) pH 9.0 (l = 1 cm, T = 25°C). Displacers were added as µl aliquots of stock solutions. Positive induced CD values measured at 278 nm are plotted against displacer/creatinine molar ratios (for further details see Materials and methods).
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pone-0017230-g007: Displacing effect of HSA site specific markers on the ICD signal of creatinine-HSA complex.Results of CD displacement experiments performed with warfarin, phenylbutazone, ibuprofen and diazepam on HSA-CTN complex at (A) pH 7.0 and (B) pH 9.0 (l = 1 cm, T = 25°C). Displacers were added as µl aliquots of stock solutions. Positive induced CD values measured at 278 nm are plotted against displacer/creatinine molar ratios (for further details see Materials and methods).

Mentions: Further spectroscopic experiments were undertaken to obtain information on the potential location of the HSA binding site of CTN. Albumin possesses two main drug binding sites, site I and II, which are located in hydrophobic cavities of subdomains IIA and IIIA, respectively [20]. In the presence of a compound having the same binding site as creatinine, amplitudes of the induced cotton effects should decrease due to competition. Therefore, CD displacement experiments were performed using four marker ligands warfarin and phenylbutazone for site I whereas ibuprofen and the benzodiazepine agent diazepam for site II. Monitoring the induced CD spectrum of creatinine during the titration showed a rapid extinction of extrinsic CD activity for both isomers of HSA but this extinction was found to be more steep at pH 9.0 (Figure 7). Especially the site I markers, phenylbutazone followed by warfarin were found to be responsible for reducing the CD signal of the protein-toxin complex to almost zero. Thereby, suggesting the direct competitive interaction between site I markers and creatinine for the binding site I. Notably, nearly complete extinction of the CD signal was achieved for both isomeric forms of HSA suggesting that the binding site was not affected by the protonation of albumin molecules.


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)

Displacing effect of HSA site specific markers on the ICD signal of creatinine-HSA complex.Results of CD displacement experiments performed with warfarin, phenylbutazone, ibuprofen and diazepam on HSA-CTN complex at (A) pH 7.0 and (B) pH 9.0 (l = 1 cm, T = 25°C). Displacers were added as µl aliquots of stock solutions. Positive induced CD values measured at 278 nm are plotted against displacer/creatinine molar ratios (for further details see Materials and methods).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017230-g007: Displacing effect of HSA site specific markers on the ICD signal of creatinine-HSA complex.Results of CD displacement experiments performed with warfarin, phenylbutazone, ibuprofen and diazepam on HSA-CTN complex at (A) pH 7.0 and (B) pH 9.0 (l = 1 cm, T = 25°C). Displacers were added as µl aliquots of stock solutions. Positive induced CD values measured at 278 nm are plotted against displacer/creatinine molar ratios (for further details see Materials and methods).
Mentions: Further spectroscopic experiments were undertaken to obtain information on the potential location of the HSA binding site of CTN. Albumin possesses two main drug binding sites, site I and II, which are located in hydrophobic cavities of subdomains IIA and IIIA, respectively [20]. In the presence of a compound having the same binding site as creatinine, amplitudes of the induced cotton effects should decrease due to competition. Therefore, CD displacement experiments were performed using four marker ligands warfarin and phenylbutazone for site I whereas ibuprofen and the benzodiazepine agent diazepam for site II. Monitoring the induced CD spectrum of creatinine during the titration showed a rapid extinction of extrinsic CD activity for both isomers of HSA but this extinction was found to be more steep at pH 9.0 (Figure 7). Especially the site I markers, phenylbutazone followed by warfarin were found to be responsible for reducing the CD signal of the protein-toxin complex to almost zero. Thereby, suggesting the direct competitive interaction between site I markers and creatinine for the binding site I. Notably, nearly complete extinction of the CD signal was achieved for both isomeric forms of HSA suggesting that the binding site was not affected by the protonation of albumin molecules.

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