<i>Response</i>
            : Scatchard Plots

Weisiger, Richard A.; Gollan, John L.; Ockner, Robert K.

doi:10.1126/science.215.4530.313

Cited by 6 publications

(13 citation statements)

References 3 publications

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“…Since dissociation is rate-limiting, uptake will reflect the bound rather than the equilibrium free concentration. This type of behavior has been observed in the perfused rat liver for bilirubin, sulfobromophthalein, long chain fatty acids, taurocholate, and rose bengal (3)(4)(5)(6)(10)(11)(12). However, the albumin concentrations used in these studies were typically lower than physiologic, and it remains to be determined if dissociation of any of these ligands is rate-limiting to uptake under physiologic conditions.…”

Section: Resultsmentioning

confidence: 58%

“…It has been proposed that these kinetics reflect the presence of sites on the liver cell surface that transiently bind albumin and catalyze the transfer of ligands from albumin to the cell. Such a mechanism has been independently supported by the demonstration of saturable binding of albumin to liver cells, and it can be shown that some form of catalyzed dissociation must exist to explain the observed rates of uptake if the published dissociation rate constants are correct (5,6). Nevertheless, the traditional model presented here remains a viable alternative to the albuminreceptor model.…”

Section: Resultsmentioning

confidence: 76%

“…3 have recently been found for long chain fatty acids (3), bile acids (4), bilirubin (11), sulfobromophthalein (10,11), and rose bengal (12). It has been proposed that these kinetics reflect the presence of sites on the liver cell surface that transiently bind albumin and catalyze the transfer of ligands from albumin to the cell.…”

Section: Resultsmentioning

confidence: 99%

“…[5] Since A must be below this value for uptake to be dissociation-limited, the range of free albumin concentrations over which uptake is limited by dissociation is given by: r2/rl < A < S/rl. [6] Since r1 is a common divisor in both the lower and upper limits, it follows that a necessary condition for such a range to exist is r2< S. [7] «<< S << r2 exist.…”

Section: Resultsmentioning

confidence: 99%

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Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.

Weisiger¹

1985

Proc. Natl. Acad. Sci. U.S.A.

151

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The hepatic uptake rate for certain albuminbound drugs and metabolites correlates poorly with their equilibrium unbound concentration in the plasma, suggesting that binding equilibrium may not always exist within the hepatic sinusoids. Currently available models for the uptake process assume binding equilibrium and, thus, cannot be used to investigate this possibility. This report presents a more general model that treats plasma-bound and free concentrations separately. A solution is provided that specifies the hepatic uptake rate as a function of the total plasma concentrations of the transported substance and of binding protein and the rate constants for influx, efflux, elimination, association, dissociation, and flow. Analysis of this solution indicates that hepatic uptake may be limited by the rate of plasma flow, dissociation from the binding protein, influx into the liver, cellular elimination, or any combination of these processes. The affinity and concentration of the binding protein strongly influence which of these steps are rate-limiting in any given case, and binding equilibrium exists within the hepatic sinusoids only for binding protein concentrations greater than a specified value (the ratio of the uptake and association rate constants). The precise conditions under which each step is rate-limiting and the kinetic behavior expected when two or more steps mutually limit uptake are provided. The results are compatible with previously reported data for the uptake of certain albuminbound ligands such as bilirubin, and they offer an alternative to attributing these kinetics to the presence of an albumin receptor.The degree to which a drug or metabolite is bound to albumin in plasma is recognized as an important determinant of its rate of removal by the liver and other tissues. Indeed, it has long been assumed that only the unbound form is available for uptake (1). This assumption is not necessarily valid, however, because the bound substance always retains some free energy (2), which makes it a potential substrate for an uptake process. Recent reports have, in fact, suggested that for several albumin-bound substances (subsequently referred to as ligands), the rate of hepatic removal correlates much more closely with the bound than with the equilibriumfree concentration (3,4). To account for these and related data, it has been proposed that uptake may occur not only from the free ligand pool, but also (less efficiently) from the bound ligand pool by a mechanism involving transient binding of albumin to receptor sites on the cell surface (5, 6). According to this model, the latter pathway predominates for tightly bound ligands such as bifirubin because of their very small unbound concentrations in plasma.Although the albumin-receptor model is attractive, it is important to consider whether the traditional view that uptake depends only on the unbound ligand concentration at the liver cell surface might not also accommodate these observations. Most traditional models assume that equilibrium exists ...

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Section: Resultsmentioning

confidence: 58%

Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.

Weisiger¹

1985

Proc. Natl. Acad. Sci. U.S.A.

151

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“…The binding and transport or free fatty acid in liver cell membranes at much lower fatty acid concentrations (less than 0.06pM) than used herein may occur via a receptor on the cell surface [36]. In contrast, at higher concentrations a simple diffusion through lipid mechanism predominates as shown by other investigators [37,38].…”

Section: Culculution Of Dissociution Constantsmentioning

confidence: 59%

Lipid Domains in Plasma Membrances from Rat Liver

Schroeder

1983

European Journal of Biochemistry

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The existence of fluid and solid lipid domains in isolated rat-liver plasma membranes was evaluated using the fluorescent fatty acids trans-parinaric and cis-parinaric acid as probe molecules for solid and Auid membrane areas, respectively. The fluorescence probe 1,6-diphenyl-l,3,5-hexatriene indicated that a phase transition was present in the liver plasma membrane between 18 "C and 30 "C. At intermediate temperatures, cis-parinaric acid, which partitioned approximately equally into fluid and soIid lipid areas, detected two lipid domains : the mole fractions of fluid and solid lipid domains at 24°C were 0.32 and 0.68 while the mole fractions of cis-parinaric acid in each domain were 0.34 and 0.66, respectively. The dissociation constant, aqueous to membrane lipid partition coefficient, and bound to free ratio for trans-parinaric acid were 7.0 0.7 pM, 4.0 & 0.6 x lo6, and 83: 17, respectively. The affinity of the membrane for cis-parinaric acid was twofold lower than for trans-parinaric acid. The trans-parinaric acid partitioned preferentially into solid lipid. K;' = 3.30, while the cis-parinaric acid partitioned equally between fluid and solid phases KJ' = 0.92. Thus, the data demonstrate the coexistence of fluid and solid domains in rat liver plasma membranes. It should be noted that the liver hepatocyte contains several different types of cell membranes. The membranes have different polarity depending on whether they are exposed to the blood circulation or to the bile. The procedure used for isolating liver plasma membrane in the present investigation largely removed the blood-front plasma membrane while purirying the bile-front area [12]. The enzymes 5'-nucleotidase and Mg-ATPase were purified 18-fold and 22-fold respectively with respect to the crude homogenate. These enzymes were assayed as described previously [14]. The Mg-ATPase was measured in the presence of ouabain. Cytochemical studies have localized Mg-ATPase to the canalicular surface [15]. The liver plasma membranes had the following lipid

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Ligand–receptor interactions: a new method for determining the binding parameters

Bobrovnik

2003

Journal of Biochemical and Biophysical Methods

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Response : Scatchard Plots

Cited by 6 publications

References 3 publications

Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.

Dissociation from albumin: a potentially rate-limiting step in the clearance of substances by the liver.

Lipid Domains in Plasma Membrances from Rat Liver

Ligand–receptor interactions: a new method for determining the binding parameters

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