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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

Correlation between uremic toxicity and impaired drug binding.Mechanism showing possible cascade displacement model in uremic toxin– drug system depicts allosteric effect of toxin when binding to site I and site II. Red colour: CTN binding to its high-affinity site, site I as shown by solid arrows; blue colour: CTN binding to its low-affinity site, site II as shown by dashed arrows. Hemodialytic reaction occurring within the blood plasma has been shown in red box.
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pone-0017230-g012: Correlation between uremic toxicity and impaired drug binding.Mechanism showing possible cascade displacement model in uremic toxin– drug system depicts allosteric effect of toxin when binding to site I and site II. Red colour: CTN binding to its high-affinity site, site I as shown by solid arrows; blue colour: CTN binding to its low-affinity site, site II as shown by dashed arrows. Hemodialytic reaction occurring within the blood plasma has been shown in red box.

Mentions: Curry et al. have determined the crystal structure of HSA complexed with five molecules of fatty acid at 2.5 Å resolution [20]. Arg 257 was found to interact with myristate bound to subdomain IIA. Similar interaction we observed with HSA-CTN complexation. It was noteworthy that the single tryptophan residue of HSA (Trp 214) was not in the immediate environment of the docked toxin molecule as proved by our spectroscopic results and was further confirmed by computational mapping approaches. Guanidino compounds are generated in vivo as a result of protein and amino acid metabolism. In general the GCs acquire the guanidino group from arginine, with subsequent methylation to creatine and further metabolization to creatinine [41]. In patients with renal impairment, several-fold increases in specific guanidino compounds were observed due to the impaired renal function and altered metabolism [6]. Most drugs are bound to serum proteins to a various degree. Only unbound or free drug is pharmacologically active. There is equilibrium between bound and free drugs, and concentration of free drug can be predicted from total drug concentration. However, under uremic conditions this equilibrium is disturbed and the measured free drug concentration can be significantly higher than expected from total drug concentrations, especially for strongly protein-bound drugs. In such case a patient may experience drug toxicity (Figure 12).


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)

Correlation between uremic toxicity and impaired drug binding.Mechanism showing possible cascade displacement model in uremic toxin– drug system depicts allosteric effect of toxin when binding to site I and site II. Red colour: CTN binding to its high-affinity site, site I as shown by solid arrows; blue colour: CTN binding to its low-affinity site, site II as shown by dashed arrows. Hemodialytic reaction occurring within the blood plasma has been shown in red box.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0017230-g012: Correlation between uremic toxicity and impaired drug binding.Mechanism showing possible cascade displacement model in uremic toxin– drug system depicts allosteric effect of toxin when binding to site I and site II. Red colour: CTN binding to its high-affinity site, site I as shown by solid arrows; blue colour: CTN binding to its low-affinity site, site II as shown by dashed arrows. Hemodialytic reaction occurring within the blood plasma has been shown in red box.
Mentions: Curry et al. have determined the crystal structure of HSA complexed with five molecules of fatty acid at 2.5 Å resolution [20]. Arg 257 was found to interact with myristate bound to subdomain IIA. Similar interaction we observed with HSA-CTN complexation. It was noteworthy that the single tryptophan residue of HSA (Trp 214) was not in the immediate environment of the docked toxin molecule as proved by our spectroscopic results and was further confirmed by computational mapping approaches. Guanidino compounds are generated in vivo as a result of protein and amino acid metabolism. In general the GCs acquire the guanidino group from arginine, with subsequent methylation to creatine and further metabolization to creatinine [41]. In patients with renal impairment, several-fold increases in specific guanidino compounds were observed due to the impaired renal function and altered metabolism [6]. Most drugs are bound to serum proteins to a various degree. Only unbound or free drug is pharmacologically active. There is equilibrium between bound and free drugs, and concentration of free drug can be predicted from total drug concentration. However, under uremic conditions this equilibrium is disturbed and the measured free drug concentration can be significantly higher than expected from total drug concentrations, especially for strongly protein-bound drugs. In such case a patient may experience drug toxicity (Figure 12).

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