Practical Aspects of the Ligand-Binding and Enzymatic Properties of Human Serum Albumin.

Abstract

Recent work with approaches like recombinant mutants and X-ray crystallography has given much new information about the ligand-binding properties of human serum albumin (HSA). The information increases the understanding of this unique transport and depot protein and could give a structural basis for the possible construction of therapeutic agents with altered HSA-binding properties. A tabulation of high-affinity binding sites for both endogenous and exogenous compounds has been made; it could be useful for the above-mentioned purpose, but it could also be of value when trying to predict potential drug interactions at the protein-binding level. Drug displacement is not always a complication to therapy; it can be used to increase the biological effect of a drug. However, due to rebinding at other sites, the increase in the free concentration of a displaced ligand can be less than expected. Drugs and drug metabolites can also interact covalently with HSA; thiol-containing drugs often bind to the single free cysteine residue of HSA, and glucuronidated drugs react irreversibly with other residues of the protein. Reversible binding of ligands is often stereospecific, and therefore immobilized HSA can be used to separate drug isomers. Albumin-containing dialysates are useful for extracorporeal removal of endogenous toxins and in the treatment of drug overdoses. HSA has different types of hydrolytic activities, which also can be stereospecific. The esterase-like property seems especially useful in converting prodrugs to active drugs in plasma.

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

“…Among others, HSA appears (1) to be an important determinant of the pharmacokinetic behavior of many drugs, (2) to account for most of the antioxidant capacity of human serum, and (3) to display enzymatic properties [1][2][3][4][5][6][7][8][9][10][11].…”

Drug binding to human serum albumin: Abridged review of results obtained with high‐performance liquid chromatography and circular dichroism

“…Human serum albumin (HSA) and a 1 -acid glycoprotein (AGP) are the most important plasma proteins, which act as drug carriers, with drug pharmacokinetic implications. [1][2][3] As the actual volume of distribution and concentration of a drug at the receptor site are strictly related to the amount of unbound drug fraction, a full characterization of the binding mechanism to proteins such as HSA and AGP has become essential to understand the pharmacokinetic, pharmacodynamic, and toxicological profile of any drug.…”

“…These phenomena are very important if the drug is tightly bound (over 90%) to HSA. [1][2][3] As an example, the concurrent administration of warfarin with phenylbutazone results in an enhanced risk of hemorrhage in patients due to higher concentration of the free anticoagulant drug because of its displacement from the shared binding site on albumin. 5 In addition, enantioselective binding can be observed if the drug is chiral, because the two diastereomeric adducts formed between the single enantiomers and the protein can have different stability.…”

“…In the case of direct competition [eq. (2)], the ratio between the affinity constants of the ligand (K m ) and of the competitor (K c ) is expressed in terms of ''relative CD'' (CD rel ), that is, the ratio between the measured CD signal in the presence of the competitor and that measured in its absence (marker alone):…”

“…Finally, glycosylation is another noncatalysed physiological reaction particularly relevant in diabetic individuals. 2 Samples of HSA were post-translationally modified according to the above reactions and analyzed by SDS-PAGE analysis. 58,59 Short wavelength CD spectra of native and modified HSA were recorded without further purification.…”