Transcellular transport of organic anions in the isolated perfused rat liver: The differential effects of monensin and colchicine

Abstract

Nonbile salt cholephiles and bile salts are two classes of organic anions that are efficiently taken up and excreted by the liver. Recent evidence suggests that a microtubular system-dependent, colchicine-sensitive transcellular pathway may transport both classes of these ligands. The relationship of this pathway to flux rates, however, remains unclear. Some structural evidence suggests an important role for a Golgi-associated vesicular system. Monensin, like colchicine, is a perturbing agent that is believed to target primarily Golgi and related organelles. The effects of a minimal effective dose of both colchicine (0.06 mg to 0.12 mg/100 gm body wt) and monensin (0.6 mg/100 gm body wt) were examined in the isolated perfused rat liver in a single-pass mode. The nonbile salt cholephile, phenol red, was studied at two doses: 1 nmol and 5 mumol. Sodium taurocholate was studied at three doses: 2 nmol, 1 mumol and 5 mumol. Colchicine affected the transcellular transport for both classes of organic anions equally. Partially inhibitory effects on both anions occurred only at high ligand flux rates. In contrast, monensin greatly impaired the transport of nonbile salt cholephiles but had no influence on transcellular bile salt flux. We conclude that the monensin effect appears to define a distinct transcellular transport pathway for each of the two classes of organic anions.

Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats

“…Aoyama et al . reported that colchicine inhibited the biliary excretion of phenol red, although its inhibitory effect was slight, 14 and Dumont et al . reported that colchicine inhibited the biliary excretion of diethymaleate‐glutathione, an Mrp2 substrate 15 .…”

“…Colchicine has also been reported to inhibit the biliary excretion of some organic anions 13–16 . However, the findings of the effect of colchicine on biliary excretion are controversial 13–16 …”

Involvement of microtubules in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver

“…In the past, evidence has been given repeatedly for a vesicular bile-acid transport facility (Dubin et al, 1980;Goldsmith et al, 1983;Kacich et al, 1983;Suchy et al, 1983;Lamri et al, 1988;Stolz et al, 1989;Dumont et al, 1991;Aoyama et al, 1991), in part based on the electron-microscopic demonstration of bile-acidcontaining vesicles inside hepatocytes (Suchy et al, 1983;Lamri et al, 1988 Such a hypothesis would predict that during the swelling-induced fusion process the bile acids concentrated inside the vesicles will be poured out into the canalicular lumen in a colchicine-sensitive way. Indeed, a biphasic stimulation of taurocholate excretion is observed after isotonic cell swelling by glutamine plus glycine (Figure 4).…”

“…Also in other cell types, evidence has been given for a rearrangement of cytoskeletal structures after anisotonic exposure (Cornet et al, 1987;Linshaw et al, 1992). Bile formation was repeatedly shown to be sensitive to inhibitors of cytoskeletal structures (for reviews see Sellinger and Boyer, 1990;Nathanson and Boyer, 1991;Boyer et al, 1992) and the existence of a vesicular bile acid transport mechanism in liver has been discussed repeatedly (Dubin et al, 1980;Kacich et al, 1983;Goldsmith et al, 1983;Suchy et al, 1983;Lamri et al, 1988;Stolz et al, 1989;Aoyama et al, 1991;Dumont et al, 1991). Thus, we addressed the question whether the cell-volume-dependence of transcellular taurocholate transport in liver is sensitive to inhibitors of microtubule formation.…”

Impairment of hepatic transport processes in perfused rat liver by the specific CCK receptor antagonist loxiglumide

“…Therefore, the hepatic extraction and excretion rates were determined in the absence and presence of loxiglumide in order to characterize the mechanism responsible for the inhibition of hepatic CCK uptake by the specific CCK receptor antagonist. Transport of bile acids in the liver involves three major mechanisms [25]: (1) uptake via multispecific, sodium-dependent transport system [1,7,13,34], (2) intracellular transport via interaction with cytoplasmic proteins [4], and (3) secretion at the canalicular membrane into bile via a sodium-independent transport system. The rate-limiting step is the canalicular bile salt secretion.…”