Competition of drugs to serum albumin in combination therapy

Biochemical and Biophysical Research Communications

Masi

Sanctis

et al. 2009

a b s t r a c tHuman serum albumin (HSA) is a monomeric allosteric protein. Here, the effect of ibuprofen on denitrosylation kinetics (k off ) and spectroscopic properties of HSA-heme-Fe(II)-NO is reported. The k off value increases from (1.4 ± 0.2) Â 10 À4 s À1 , in the absence of the drug, to (9.5 ± 1.2) Â 10 À3 s À1 , in the presence of 1.0 Â 10 À2 M ibuprofen, at pH 7.0 and 10.0°C. From the dependence of k off on the drug concentration, values of the dissociation equilibrium constants for ibuprofen binding to HSA-heme-Fe(II)-NO (K 1 = (3.1 ± 0.4) Â 10 À7 M, K 2 = (1.7 ± 0.2) Â 10 À4 M, and K 3 = (2.2 ± 0.2) Â 10 À3 M) were determined. The K 3 value corresponds to the value of the dissociation equilibrium constant for ibuprofen binding to HSA-heme-Fe(II)-NO determined by monitoring drug-dependent absorbance spectroscopic changes (H = (2.6 ± 0.3) Â 10 À3 M). Present data indicate that ibuprofen binds to the FA3-FA4 cleft (Sudlow's site II), to the FA6 site, and possibly to the FA2 pocket, inducing the hexa-coordination of HSA-heme-Fe(II)-NO and triggering the heme-ligand dissociation kinetics.

mentioning

confidence: 99%

“…Bulky heterocyclic molecules (e.g., warfarin) bind preferentially to Sudlow's site I, whereas Sudlow's site II is preferred by aromatic carboxylates with an extended conformation (e.g., ibuprofen) [1][2][3][5][6][7][8][9][10][11][12][13][14]26,[31][32][33][34][35][36].…”

mentioning

confidence: 99%

Ibuprofen modulates allosterically NO dissociation from ferrous nitrosylated human serum heme-albumin by binding to three sites

Biochemical and Biophysical Research Communications

Masi

Sanctis

et al. 2009

“…Human serum albumin (HSA), the most prominent protein in plasma, provides a depot and carrier for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders harmless potential toxins transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and displays (pseudo-)enzymatic properties [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

mentioning

confidence: 99%

“…Heme propionates point towards the interface between domains I and III and are stabilized by salt bridges with His146 and Lys190 [18,19]. Bulky heterocyclic molecules bind preferentially to Sudlow's site I, whereas Sudlow's site II is preferred by aromatic carboxylates with an extended conformation [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]20].…”

mentioning

confidence: 99%

Abacavir and warfarin modulate allosterically kinetics of NO dissociation from ferrous nitrosylated human serum heme-albumin

Biochemical and Biophysical Research Communications

Imperi

Coletta

et al. 2008

Human serum albumin (HSA) participates to heme scavenging, in turn HSA-heme binds gaseous diatomic ligands at the heme-Featom. Here, the effect of abacavir and warfarin on denitrosylation kinetics of HSA-heme-Fe(II)-NO (i.e., k off ) is reported. In the absence of drugs, the value of k off is (1.3 ± 0.2) Â 10 À4 s À1 . Abacavir and warfarin facilitate NO dissociation from HSA-heme-Fe(II)-NO, the k off value increases to (8.6 ± 0.9) Â 10 À4 s À1 . From the dependence of k off on the drug concentration, values of the dissociation equilibrium constant for the abacavir and warfarin binding to HSA-heme-Fe(II)-NO (i.e., K = (1.2 ± 0.2) Â 10 À3 M and (6.2 ± 0.7) Â 10 À5 M, respectively) were determined. The increase of k off values reflects the stabilization of the basic form of HSA-heme-Fe by ligands (e.g., abacavir and warfarin) that bind to Sudlow's site I. This event parallels the stabilization of the six-coordinate derivative of the HSAheme-Fe(II)-NO atom. Present data highlight the allosteric modulation of HSA-heme-Fe(II) reactivity by heterotropic effectors.

“…Serum albumin (SA), the most abundant protein in plasma, is characterized by an extraordinary ligand-binding capacity that provides a depot and carrier for many compounds, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless by transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and displays (pseudo-)enzymatic properties (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Serum heme‐albumin: An allosteric protein

Fasano

2009

IUBMB Life

SummaryHeme scavenging by plasma proteins, including serum albumin (SA), provides protection against free-heme oxidative damage, limits access by pathogens to the heme, and contributes to iron homeostasis by recycling the heme iron. In turn, serum heme-albumin (SA-heme) acquires heme-based ligand-binding and (pseudo-)enzymatic properties. Heme binding to SA and SA-heme reactivity are allosterically and competitively modulated by endogenous and exogenous third components, this being relevant in pharmacotherapy management.