A NOVEL TRANSCELLULAR TRANSPORT PATHWAY FOR NONBILE SALT CHOLEPHILIC ORGANIC-ANIONS

Non-bile salt cholephilic organic anions comprise a single class of nonhomologous ligands having a range of hydrophobicity. Hydrophobicity enhances the hepatic extraction of cholephiles as well as their partitioning into secreted biliary lipid particles. When hydrophobicity is correlated with patterns of biliary excretion for studying transcellular transport, however, the more hydrophobic probes are unsuitable. Specifically, with the isolated perfused rat liver technique, the excretory times for sulfobromophthalein and rose bengal were significantly longer compared with that for the much more hydrophilic analogue phenol red (PR), which showed only a single, nearly symmetrical excretory peak at 10 min. Colchicine affected the apparently well-defined PR pathway only at a saturation dose (10,000 times the tracer dose). In contrast, the effect of a different perturbant, monensin, was striking at a tracer dose of PR, but was less evident at a saturation dose. The combined administration of colchicine and monensin had no additive inhibitory effect on PR excretion at tracer doses. At a saturation dose of PR, where monensin is less inhibiting, however, a significant additive inhibitory effect was observed. The effect of monensin compared with colchicine on the excretory profile of horseradish peroxidase (HRP) was to inhibit an earlier, i.e., approximately 8-15 min, separate pathway or an early component of the classical HRP pathway, whereas the combined effect of these two perturbants resulted in a marked exaggeration of the early "paracellular" pathway peak. This suggested a dual but separate inhibition of later pathways used by HRP for vesicular transport. The data are compatible with the existence of a specific monensin-sensitive, colchicine-insensitive pathway for transcellular transport of non-bile salt cholephilic organic anions.