THE SINUSOIDAL EFFLUX OF DIBROMOSULFOPHTHALEIN FROM RAT-LIVER IS STIMULATED BY ALBUMIN, LIGANDIN AND FATTY-ACID-BINDING PROTEIN BUT NOT BY OTHER DIBROMOSULFOPHTHALEIN BINDING-PROTEINS
Hmj. Nijssen et al., THE SINUSOIDAL EFFLUX OF DIBROMOSULFOPHTHALEIN FROM RAT-LIVER IS STIMULATED BY ALBUMIN, LIGANDIN AND FATTY-ACID-BINDING PROTEIN BUT NOT BY OTHER DIBROMOSULFOPHTHALEIN BINDING-PROTEINS, Journal of hepatology, 21(1), 1994, pp. 29-36
Organic anions can be excreted from the liver into the bile or back in
to the general circulation (sinusoidal efflux). It has previously been
shown that the net sinusoidal efflux rate of dibromosulfophthalein fr
om the perfused liver into the perfusate is the result of actual efflu
x from and reuptake into the liver, and can be strongly influenced by
the presence of bovine serum albumin in the perfusion medium. The pres
ent study investigated whether the influence of albumin on the net sin
usoidal efflux process is albumin-specific or whether other binding pr
oteins could have a similar effect on the sinusoidal efflux. Using a s
ingle-pass liver perfusion technique and short-lasting (pulse) protein
infusions, the stimulatory effect of a wide range of dibromosulfophth
alein binding proteins on the sinusoidal efflux process were determine
d. These experiments showed that all the serum albumins tested as well
as the liver cytosolic binding proteins fatty acid binding protein an
d ligandin (glutathione S-transferase) stimulated this process. The ot
her proteins tested, bovine beta lactoglobulin-b, human gamma globulin
and chicken egg lysozyme showed no stimulatory effect, despite relati
vely high equilibrium binding of dibromosulfophthalein. No clear-cut r
elationship was found between the equilibrium unbound ligand concentra
tion as measured in perfusate and the stimulatory effect, suggesting a
bsence of equilibrium binding in the sinusoids. Equilibrium binding of
dibromosulfophthalein to chicken serum albumin and ligandin as well a
s the dissociation rate constants were determined in vitro with rapid
filtration techniques. Pharmacokinetic modeling using a series compart
ment model showed that the stimulatory effect of these proteins could
only be simulated accurately with higher values for both the associati
on and dissociation rate constants compared with those determined in v
itro, as was previously also found for bovine serum albumin. This may
imply altered binding characteristics of the proteins during passage t
hrough the liver and/or a direct effect on the carrier-mediated efflux
process. (C) Journal of Hepatology.