The effect of albumin conformation on the binding of warfarin to human serum albumin. The dependence of the binding of warfarin to human serum albumin on the hydrogen, calcium, and chloride ion concentrations as studied by circular dichroism, fluorescence, and equilibrium dialysis.

Wilting, Jaap; Giesen, Willem F. van der; Janssen, Lambert H.M.; Weideman, Margie M.; Otagiri, Masaki; Perrin, John H.

doi:10.1016/s0021-9258(19)85847-7

Cited by 217 publications

(17 citation statements)

References 39 publications

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“…42,43 This could be explained due to the changes in molecular conformation of albumin on binding with small molecules, which also change with the pH of solution leading to increased formation of β-sheets and random coil structures at the expense of the α-helix. 47,48 This may also suggest formation of more inter and intradomain structures when MRN interacts or binds with HSA. This test was a supplement to our molecular docking studies to indicate that there was an interaction between the MRN and HSA, given that this has not been reported in literature earlier.…”

Section: ■ Discussionmentioning

confidence: 99%

“…However, this change in secondary structure was not observed at other HSA/MRN molar ratios and at other different pH conditions. This can be compared with changes observed in the HSA secondary structure on binding with drug molecules such as virstatin or cisplatin. , This could be explained due to the changes in molecular conformation of albumin on binding with small molecules, which also change with the pH of solution leading to increased formation of β-sheets and random coil structures at the expense of the α-helix. , This may also suggest formation of more inter and intradomain structures when MRN interacts or binds with HSA. This test was a supplement to our molecular docking studies to indicate that there was an interaction between the MRN and HSA, given that this has not been reported in literature earlier.…”

Section: Discussionmentioning

confidence: 99%

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Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization

Lomis¹,

Gaudreault

Malhotra

et al. 2017

Mol. Pharmaceutics

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Cardiovascular diseases are the leading causes of mortality across the globe. Over the years, various drug formulations and delivery methods have been tested for cardiac repair. Milrinone (MRN) is a widely known cardiac inotrope drug used for the treatment of congestive heart failure in patients, however, its efficacy is limited. This study is the first to report the design of a novel MRN-nanoformulation using human serum albumin nanoparticles (HSA-NPs). The HSA-NPs exhibit promising drug delivery characteristics, such as target specificity, nonimmunogenicity, biocompatibility, and enhanced bioavailability. This article describes a MRN-nanoformulation design for in vitro drug release, cellular uptake, biocompatibility, and other features. The MRN-nanoformulation was prepared by the ethanol desolvation technique and key parameters were optimized to obtain a desired particle size of 154.2 ± 5.8 nm, zeta potential of -29.5 ± 2.9 mV, and a drug encapsulation efficiency of 41.1 ± 1.7%. Molecular docking studies have revealed that MRN binds in the hydrophobic cavity of HSA, which has also been indicated by circular dichroism and enzyme-mediated drug release studies in the presence of trypsin, pepsin, proteinase K, protease, and cathepsin D. The intracellular uptake of fluorescently tagged MRN-HSA-NPs using HUVEC and H9c2 cells was evaluated by flow cytometry. The nanoparticle toxicity results indicated that MRN-HSA-NPs show significantly lower cytotoxicity and higher cell viability ( P < 0.0001) as compared to the MRN-lactate drug in HUVEC (61.6 ± 3.7% vs 36.2 ± 2.9%) and H9c2 (58.8 ± 5.7% vs 18.8 ± 4.9%) cells. These studies indicate that the novel MRN-nanoformulation offers better drug delivery procedures than currently used methods and has potential in treatment of congestive heart failure and other cardiovascular diseases.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization

Lomis¹,

Gaudreault

Malhotra

et al. 2017

Mol. Pharmaceutics

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“…Several attempts have been made to find a test for the transport function and a function-structure-relation 1 , 2 . In in vitro studies, equilibrium dialysis is often used to investigate the binding of small molecules to HSA 3 , while ultrafiltration techniques and titration curves are used to determine binding and dissociation constants of compounds 4 , 5 . The binding of spin-labeled fatty acids (FA) at different concentrations and with the addition of various amounts of ethanol is used to determine the detoxification and binding efficiency of albumin 2 .…”

Section: Introductionmentioning

confidence: 99%

Albumin in patients with liver disease shows an altered conformation

et al. 2021

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Human serum albumin (HSA) constitutes the primary transporter of fatty acids, bilirubin, and other plasma compounds. The binding, transport, and release of its cargos strongly depend on albumin conformation, which is affected by bound ligands induced by physiological and pathological conditions. HSA is both highly oxidized and heavily loaded with fatty acids and bilirubin in chronic liver disease. By employing small-angle X-ray scattering we show that HSA from the plasma of chronic liver disease patients undergoes a distinct opening compared to healthy donors. The extent of HSA opening correlates with clinically relevant variables, such as the model of end-stage liver disease score, bilirubin, and fatty acid levels. Although the mild oxidation of HSA in vitro does not alter overall structure, the alteration of patients’ HSA correlates with its redox state. This study connects clinical data with structural visualization of albumin dynamicity in solution and underlines the functional importance of albumin’s inherent flexibility.

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“…Though the pH of human blood is generally stable, pH fluctuations are not unusual in various intracellular and extracellular milieus where drug–HSA interactions occur. − Thus, such pH-dependent conformational transitions of HSA can potentially influence the drug–HSA interaction. It may also lead to alteration of the effective drug concentration in the blood consequently affecting its physiological function. , Furthermore, the physiological relevance of the N ⇌ B transition can be understood from the predominance of the B-isoform of HSA under enhanced concentration of Ca 2+ ions in the plasma . Additionally, the N ⇌ B transition (or transition analogous to this) has been argued to play crucial regulatory roles underlying the transport function of the protein. − …”

Section: Introductionmentioning

confidence: 99%

“…It may also lead to alteration of the effective drug concentration in the blood consequently affecting its physiological function. , Furthermore, the physiological relevance of the N ⇌ B transition can be understood from the predominance of the B-isoform of HSA under enhanced concentration of Ca 2+ ions in the plasma . Additionally, the N ⇌ B transition (or transition analogous to this) has been argued to play crucial regulatory roles underlying the transport function of the protein. − …”

Section: Introductionmentioning

confidence: 99%

Contrasting Thermodynamics Governs the Interaction of 3-Hydroxyflavone with the N-Isoform and B-Isoform of Human Serum Albumin

et al. 2020

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Herein we report the interaction of 3-hydroxyflavone (3HF) with various isomeric forms of Human Serum Albumin (HSA), namely, the N-isoform (or native HSA at pH 7.4) and the B-isoform (at pH 9.2). Spectroscopic signatures of 3HF reveal that the interaction of 3HF with the N-isoform of HSA results in significant lowering of absorbance of the neutral species (λabs ∼ 345 nm) with concomitant increase of the anionic species (λabs ∼ 416 nm) whereas interaction with the B-isoform of HSA leads to selective enhancement of absorbance of the anionic species. The fluorescence profile of 3HF displays marked increase of intensity of the proton transferred tautomer (λem ∼ 538 nm) as well as the anionic species (λem ∼ 501 nm) for both the forms of the protein. However, analyses of the associated thermodynamics through temperature-dependent isothermal titration calorimetric (ITC) indicate that the interaction of 3HF with the N-isoform of HSA is more enthalpic in the lower temperature limit while the entropy contribution predominates in the higher temperature limit. Consequently, the 3HF–HSA (N-isoform at pH 7.4) interaction reveals an unusual thermodynamic signature of a positive heat capacity change (ΔC p = 3.84 kJ mol–1K–1) suggesting the instrumental role of hydrophobic hydration. On the contrary, the 3HF–HSA (B-isoform at pH 9.2) interaction shows qualitatively reverse effect. Consequently, the interaction is found to be characterized by an enthalpy-dominated hydrophobic effect (negative heat capacity change, ΔC p = −1.15 kJ mol–1K–1) which is rationalized on the basis of the nonclassical hydrophobic effect.

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The effect of albumin conformation on the binding of warfarin to human serum albumin. The dependence of the binding of warfarin to human serum albumin on the hydrogen, calcium, and chloride ion concentrations as studied by circular dichroism, fluorescence, and equilibrium dialysis.

Cited by 217 publications

References 39 publications

Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization

Novel Milrinone Nanoformulation for Use in Cardiovascular Diseases: Preparation and in Vitro Characterization

Albumin in patients with liver disease shows an altered conformation

Contrasting Thermodynamics Governs the Interaction of 3-Hydroxyflavone with the N-Isoform and B-Isoform of Human Serum Albumin

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