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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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The acidic-basic equilibrium of creatinine.In aqueous solution creatinine exists in the form of a tautomer.
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pone-0017230-g010: The acidic-basic equilibrium of creatinine.In aqueous solution creatinine exists in the form of a tautomer.

Mentions: The question arises which binding sites on the albumin molecule were usually affected by creatinine? Data for the binding ability of albumin before and after its loading with uremic toxin with marker ligand specific for sites I and II were represented by displacement experiments as shown in Figure 7. The site I markers at pH 7 and 9 reduces the induced CD signal to almost zero. The association constant of phenylbutazone was Ka 7×105 M−1, n = 1 and warfarin was Ka = 3.3×105 M−1, n = 1 [20] and that for CTN (after exciting the protein at 280 nm) was Ka = 1.4×105 M−1, n≈1 (Table 2) the site I markers can displace CTN from its binding site on albumin. The association constant for diazepam (Ka = 3.8×105 M−1, n = 1) and ibuprofen (Ka = 2.7×105 M−1, n = 1) [20] was higher than that for CTN and lower than that for site I markers. Site II markers were, therefore, likely to weak inhibitors of the binding of CTN. Thus, fluorescence quenching and induced CD spectrums were utilized to achieve three goals (i) calculating the association constant (Ka) (ii) determining the dependence of toxin binding on albumin conformation and (iii) probing the location of uremic toxin binding site on HSA. Furthermore, CTN possesses two pKa values of 4.88 for protonation [40] and 12.7–13.4 for deprotonation of the exocyclic amino group. This suggests that CTN predominantly occurs in aqueous solution and in blood plasma at pH 7.4 in neutral form. In aqueous solution it exists in the form of a tautomer, its acido–basic equilibrium has been shown in Figure 10. When analyzing the accessible surface area we found main involvement of arginine residues in the toxin complexation with albumin (Table 4). This change seemed to be caused by His residues because most of the pKa values of His residues are within this pH region i.e. 6.4. Thus, during alkalization of HSA, the affinity of CTN increases. On the onset of pH 9.0, the Arg residues involved in binding protonate (pKa of Arg  = 9.04 (NH3+) and 12.04 (side chain)), and then may interact favorably with the toxin. Whilst at pH 7.0, deprotonation weakens the interaction with the cation.


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)

The acidic-basic equilibrium of creatinine.In aqueous solution creatinine exists in the form of a tautomer.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017230-g010: The acidic-basic equilibrium of creatinine.In aqueous solution creatinine exists in the form of a tautomer.
Mentions: The question arises which binding sites on the albumin molecule were usually affected by creatinine? Data for the binding ability of albumin before and after its loading with uremic toxin with marker ligand specific for sites I and II were represented by displacement experiments as shown in Figure 7. The site I markers at pH 7 and 9 reduces the induced CD signal to almost zero. The association constant of phenylbutazone was Ka 7×105 M−1, n = 1 and warfarin was Ka = 3.3×105 M−1, n = 1 [20] and that for CTN (after exciting the protein at 280 nm) was Ka = 1.4×105 M−1, n≈1 (Table 2) the site I markers can displace CTN from its binding site on albumin. The association constant for diazepam (Ka = 3.8×105 M−1, n = 1) and ibuprofen (Ka = 2.7×105 M−1, n = 1) [20] was higher than that for CTN and lower than that for site I markers. Site II markers were, therefore, likely to weak inhibitors of the binding of CTN. Thus, fluorescence quenching and induced CD spectrums were utilized to achieve three goals (i) calculating the association constant (Ka) (ii) determining the dependence of toxin binding on albumin conformation and (iii) probing the location of uremic toxin binding site on HSA. Furthermore, CTN possesses two pKa values of 4.88 for protonation [40] and 12.7–13.4 for deprotonation of the exocyclic amino group. This suggests that CTN predominantly occurs in aqueous solution and in blood plasma at pH 7.4 in neutral form. In aqueous solution it exists in the form of a tautomer, its acido–basic equilibrium has been shown in Figure 10. When analyzing the accessible surface area we found main involvement of arginine residues in the toxin complexation with albumin (Table 4). This change seemed to be caused by His residues because most of the pKa values of His residues are within this pH region i.e. 6.4. Thus, during alkalization of HSA, the affinity of CTN increases. On the onset of pH 9.0, the Arg residues involved in binding protonate (pKa of Arg  = 9.04 (NH3+) and 12.04 (side chain)), and then may interact favorably with the toxin. Whilst at pH 7.0, deprotonation weakens the interaction with the cation.

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