DRUG INTERACTIONS—PART II

PEDIATRICS ◽  
1972 ◽  
Vol 49 (6) ◽  
pp. 916-918
Author(s):  
Leo Stern
Keyword(s):  
Binding Sites ◽  
Unconjugated Bilirubin ◽  
Albumin Binding ◽  
Nonesterified Fatty Acids ◽  
Factors Affecting ◽  
Spectral Curves ◽  
Low Levels ◽  
Bilirubin Binding ◽  
Direct Acting

Unlike its conjugated (direct acting) counterpart, unconjugated (indirect acting) bilirubin is insoluble in water, but highly soluble in lipids. Hence, it tends to diffuse out of plasma into the lipid-rich CNS with resultant kernicterus. This does not occur when unconjugated bilirubin is bound to albumin, as the complex is too large for diffusion. The production of kernicterus thus involves the increase of free, unbound, unconjugated bilirubin in plasma, either by dissociation from its albumin binding sites or by the introduction of one or more anions which compete preferentially for a common or shared site, thus displacing the bilirubin from its albumin bond. FACTORS AFFECTING BINDING Lowering the pH promotes bilirubin-albumin dissociation,1 and acidosis has thus been implicated as a factor in kernicterus occurring at low levels of serum bilirubin.2-5 In addition, competition for bilirubin binding sites is exhibited by a number of endogenously occurring substances as well as exogenously administered agents. Both hematin (increased in hemolytic states) and the nonesterified fatty acids (increased under conditions of both hypothermia6 and hypoglycemia7 are capable of displacing bilirubin from its albumin binding sites. In addition, a number of drugs, among which sulfisoxazole (Gantrisin) is the most widely known in view of both its clinical8 and experimental9 production of kernicterus in this fashion, are capable of causing similar displacement in vitro. Among the techniques employed to demonstrate an increase in free bilirubin is the measurement of displacement of spectral curves.10,7 The technique depends on a difference in absorbance of free (420 to 440 nm) versus bound (460 to 465 nm) bilirubin, with changes in the shapes of the curves as the amounts of free and bound bilirubin are altered.

Fixed Drug Combinations and the Displacement of Bilirubin from Albumin

PEDIATRICS ◽  
1971 ◽  
Vol 48 (1) ◽  
pp. 139-141 ◽  
Author(s):  
D. Schiff ◽  
C. Chan ◽  
L. Stern
Keyword(s):  
Premature Infants ◽  
Binding Sites ◽  
Serum Bilirubin ◽  
Albumin Binding ◽  
Fixed Drug ◽  
The Central Nervous System ◽  
Respiratory Stimulant ◽  
Low Levels

Silverman and associates,1 reported that the use of sulfisoxazole (Gantrisin) in premature infants resulted in the occurrence of kernicterus at low levels of serum bilirubin. Odell2 subsequently demonstrated that sulfisoxazole displaces bilirubin from its albumin binding sites in vitro, thereby making available lipid soluble free bilirubin capable of penetrating the central nervous system. This effect of sulfisoxazole in producing kernicterus has been confirmed experimentally in vivo in rats.3 Odell4 and Khanna, et al.5 have demonstrated a similar but quantitatively even greater bilirubin displacing effect of caffeine sodium benzoate, a drug still recommended by some as a respiratory stimulant for the newborn.

Plasma protein homocysteinylation in uremia

2007 ◽  
Vol 45 (12) ◽  
Author(s):  
Alessandra F. Perna ◽  
Filomena Acanfora ◽  
Maria Grazia Luciano ◽  
Paola Pulzella ◽  
Rosanna Capasso ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Binding Sites ◽  
Free Amino ◽  
Protein S ◽  
Hemodialysis Patients ◽  
Cysteine Residues ◽  
Albumin Binding ◽  
Amino Groups ◽  
Homocysteine Thiolactone

AbstractProtein homocysteinylation is proposed as one of the mechanisms of homocysteine toxicity. It occurs through various means, such as the post-biosynthetic acylation of free amino groups (protein-N-homocysteinylation, mediated by homocysteine thiolactone) and the formation of a covalent -S-S- bond found primarily with cysteine residues (protein-S-homocysteinylation). Both protein modifications are a cause of protein functional derangements. Hemodialysis patients in the majority of cases are hyperhomocysteinemic, if not malnourished. Protein-N-homocysteinylation and protein-S-homocysteinylation are significantly increased in hemodialysis patients compared to controls. Oral folate treatment normalizes protein-N-homocysteinylation levels, while protein-S-homocysteinylation is significantly reduced. Albumin binding experiments after in vitro homocysteinylation show that homocysteinylated albumin is significantly altered at the diazepam, but not at the warfarin and salicilic acid binding sites.Clin Chem Lab Med 2007;45:1678–82.

scholarly journals Albumin binding of photobilirubin II

1983 ◽  
Vol 213 (1) ◽  
pp. 25-29 ◽  
Author(s):  
P Meisel ◽  
K E Biebler ◽  
A Gens ◽  
K Jaehrig
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Albumin Binding ◽  
Minor Importance ◽  
High Affinity ◽  
Bilirubin Binding ◽  
Source Of Error ◽  
Single Binding Site ◽  
Site Binding

Photobilirubin II, a stereoisomer of bilirubin, binds to human serum albumin at a single binding site (K = 2.2 × 10(6)M-1), presumably the high-affinity bilirubin-binding site. Binding in the secondary (class II) binding sites is of minor importance. The results are discussed with respect to photometabolism of bilirubin and as a possible source of error in the determination of bilirubin unbound to albumin.

Do nonesterified fatty acids displace thyroxin from its plasma binding sites in severe nonthyroidal illnesses?

1989 ◽  
Vol 35 (6) ◽  
pp. 931-934 ◽  
Author(s):  
R E Nicolson ◽  
C P Reilly ◽  
P R Pannall ◽  
L Esposito ◽  
M L Wellby
Keyword(s):  
Fatty Acids ◽  
Binding Sites ◽  
Binding Proteins ◽  
The Other ◽  
Plasma Binding ◽  
Plasma Nefa ◽  
Nonesterified Fatty Acids ◽  
Very High

Abstract Severe nonthyroidal illnesses have been associated with increases in nonesterified fatty acids (NEFA) and the dialyzable fraction of thyroxin (T4) in plasma. We have further investigated their possible relationship in severe nonthyroidal illnesses as well as in induced in vivo and in vitro situations involving increased NEFA. We demonstrate that there is no relationship between NEFA and the dialyzable fraction of T4, either in severe nonthyroidal illnesses or in the other situations, unless plasma NEFA concentrations exceed 5 mmol/L in normal persons or 1.7 mmol/L in nonthyroidal illnesses, and that this concentration was not reached in the patients we studied, with one exception. We conclude that NEFA are unlikely to contribute to an inhibition of the binding of T4 to the binding proteins that might be present in plasma of patients with severe nonthyroidal illnesses unless their NEFA concentrations are very high.

Tryptophan and depressive illness

1978 ◽  
Vol 8 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Alec Coppen ◽  
Keith Wood
Keyword(s):  
Binding Sites ◽  
Plasma Proteins ◽  
Depressive Illness ◽  
Albumin Binding ◽  
Protein Binding Sites ◽  
Depressed Patients ◽  
Free Tryptophan ◽  
Esterified Fatty Acids ◽  
Low Levels ◽  
Post Menopausal

SynopsisPlasma free tryptophan is significantly decreased in monopolar, depressed patients. No evidence was found to suggest that poor nutritional history prior to hospital admission was responsible for these low levels. Factors known to influence tryptophan—albumin binding in plasma, e.g. concentration of plasma proteins, albumin and non-esterified fatty acids, did not account for the low levels of free tryptophan in depressed patients. A significant decrease in plasma free tryptophan levels was found in perimenopausal but not in pre- or post-menopausal female controls. This mirrors the decrease in circulating oestrogens. Although exogenously administered oestrogens do not have any therapeutic efficacy in relieving mild residual depressive symptoms of lithium treated patients, they increased the levels of plasma free tryptophan. Clofibrate also displaces tryptophan from plasma protein binding sites in both depressed patients and controls. Utilization of the increased levels of plasma free tryptophan is reduced in depressed patients. A situation therefore exists in depressed patients where the plasma free tryptophan is not only reduced but also leaves the plasma less readily than in control subjects.

Enhanced Increases in Cytosolic Ca2+ in ADP-Stimulated Platelets from Patients with Delta-Storage Pool Deficiency – A Possible Indicator of Interactions between Granule-Bound ADP and the Membrane ADP Receptor

1997 ◽  
Vol 77 (02) ◽  
pp. 376-382 ◽  
Author(s):  
Bruce Lages ◽  
Harvey J Weiss
Keyword(s):  
Platelet Rich Plasma ◽  
Limited Range ◽  
Dense Granule ◽  
Receptor Desensitization ◽  
Fura 2 ◽  
Storage Pool ◽  
Low Levels ◽  
The Right

SummaryThe possible involvement of secreted platelet substances in agonist- induced [Ca2+]i increases was investigated by comparing these increases in aspirin-treated, fura-2-loaded normal platelets and platelets from patients with storage pool deficiencies (SPD). In the presence and absence of extracellular calcium, the [Ca2+]i response induced by 10 µM ADP, but not those induced by 0.1 unit/ml thrombin, 3.3 µM U46619, or 20 µM serotonin, was significantly greater in SPD platelets than in normal platelets, and was increased to the greatest extent in SPD patients with Hermansky-Pudlak syndrome (HPS), in whom the dense granule deficiencies are the most severe. Pre-incubation of SPD-HPS and normal platelets with 0.005-5 µM ADP produced a dose-dependent inhibition of the [Ca2+]i response induced by 10 µ M ADP, but did not alter the [Ca2+]i increases induced by thrombin or U46619. Within a limited range of ADP concentrations, the dose-inhibition curve of the [Ca2+]i response to 10 µM ADP was significantly shifted to the right in SPD-HPS platelets, indicating that pre-incubation with greater amounts of ADP were required to achieve the same extent of inhibition as in normal platelets. These results are consistent with a hypothesis that the smaller ADP-induced [Ca2+]i increases seen in normal platelets may result from prior interactions of dense granule ADP, released via leakage or low levels of activation, with membrane ADP receptors, causing receptor desensitization. Addition of apyrase to platelet-rich plasma prior to fura-2 loading increased the ADP-induced [Ca2+]i response in both normal and SPD-HPS platelets, suggesting that some release of ADP derived from both dense granule and non-granular sources occurs during in vitro fura-2 loading and platelet washing procedures. However, this [Ca2+]i response was also greater in SPD-HPS platelets when blood was collected with minimal manipulation directly into anticoagulant containing apyrase, raising the possibility that release of dense granule ADP resulting in receptor desensitization may also occur in vivo. Thus, in addition to enhancing platelet activation, dense granule ADP could also act to limit the ADP-mediated reactivity of platelets exposed in vivo to low levels of stimulation.

EVALUATION OF TISSUE STEROID BINDING IN VITRO

1971 ◽  
Vol 68 (1_Suppl) ◽  
pp. S223-S246 ◽  
Author(s):  
C. R. Wira ◽  
H. Rochefort ◽  
E. E. Baulieu
Keyword(s):  
Protein Binding ◽  
Binding Sites ◽  
Experimental System ◽  
Specific Protein ◽  
Coupling Mechanism ◽  
Target Tissue ◽  
Protein Binding Sites ◽  
Definition Of ◽  
Hormone Specificity

ABSTRACT The definition of a RECEPTOR* in terms of a receptive site, an executive site and a coupling mechanism, is followed by a general consideration of four binding criteria, which include hormone specificity, tissue specificity, high affinity and saturation, essential for distinguishing between specific and nonspecific binding. Experimental approaches are proposed for choosing an experimental system (either organized or soluble) and detecting the presence of protein binding sites. Techniques are then presented for evaluating the specific protein binding sites (receptors) in terms of the four criteria. This is followed by a brief consideration of how receptors may be located in cells and characterized when extracted. Finally various examples of oestrogen, androgen, progestagen, glucocorticoid and mineralocorticoid binding to their respective target tissues are presented, to illustrate how researchers have identified specific corticoid and mineralocorticoid binding in their respective target tissue receptors.

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