Role of ligandin in transfer of bilirubin from plasma into liver.

Abstract

Multiple-indicator dilution studies of labeled bilirubin uptake were carried out on isolated perfused rat livers with variable ligandin concentrations (from normal and thyroidectomized animals with and without phenobarbital pretreatment). Ligandin concentrations, measured immunologically, increased 25% after thyroidectomy and approximately doubled after phenobarbital pretreatment but decreased to normal during perfusion in the thyroidectomized nonpretreated group. A distributed two-compartment model was fitted to the dilution data and estimates of influx, efflux, and sequestration coefficients were obtained. Influx and sequestration coefficients did not vary significantly between the groups. Efflux coefficients were significantly smaller (P less than 0.001), and hepatic ligandin concentrations were significantly larger (p less than 0.001) in phenobarbital-treated rats than in other groups. The efflux coefficient varied inversely with ligandin concentration and the volume of distribution in tissue, as perceived from the plasma space, increased in proportion to the concentration of ligandin. The increased net uptake of tracer bilirubin by the liver of phenobarbital-pretreated animals is due to decreased tracer efflux secondary to the increase in intracellular binding of bilirubin by ligandin.

Influence of glutathione S-transferase B (ligandin) on the intermembrane transfer of bilirubin. Implications for the intracellular transport of nonsubstrate ligands in hepatocytes.

“…In this capacity, it is postulated that GST serve a cytoprotective role by decreasing the partitioning of hydrophobic and amphipathic molecules into cellular membranes. Other investigators have shown that the presence of high intracellular concentrations of GST facilitates net uptake of nonsubstrate ligands into the hepatocyte by decreasing ligand efflux from the cell (1,12,59,60), although these observations have been challenged (61). It is notable that various xenobiotic compounds have been demonstrated to modulate GST gene expression in a host of tissues, including the liver (44,62,63).…”

Identification, Purification, and Partial Characterization of an Organic Anion Binding Protein from Rat Liver Cell Plasma Membrane

“…After the intravenous injection of tracer amounts of [3H]bilirubin or [35S]BSP in rats, -40% of injected radioactivity is present within the liver 1.5 min later (2,(4)(5)(6). In the isolated perfused rat liver, 30 '251-albumin is injected simultaneously, all 1251 is recovered in the hepatic vein effluent confirming that albumin does not accompany bilirubin or BSP into the liver cell (7,8).…”

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

“…BR, however, is not a substrate for glutathione conjugation. The binding to GSTs reduces the efflux of BR from hepatocytes increasing its net uptake (Kamisaka et al, 1975;Wolkoff et al, 1978Wolkoff et al, , 2012. BR is then converted into mono-and di-glucuronide predominantly by a single uridine diphosphoglucuronate glucuronosyltransferase (UGTs) isoform, UGT1A1 (Bosma et al, 1994).…”

“…While both strains are widely used in drug metabolism studies, strain characteristics might explain differences in responsiveness to certain inducing agents. For example, differences in glutathione S-transferase activity (GST) may alter net uptake of BR by hepatocytes (Wolkoff et al, 1978(Wolkoff et al, , 2012Higgins and Hayes, 2011). Furthermore, it has been reported that DBA/2 mice lack functional…”