Search

Diethyl maleate (DEM) induces a choleresis in the rat and dog that appears to be canalicular in origin (bile flow and erythritol clearance increase equally) and occurs in the absence of an increase in bile salt excretion. Increased bile flow is probably accounted for by the osmotic activity of DEM compounds excreted into bile. These compounds represent the glutathione conjugate of DEM (DEM-GSH) and its subsequent metabolic products. Conjugation of DEM largely accounts for the depletion of hepatic GSH.

Uptake of iopanoic acid (IOP) was studied in 3-day primary cultures of rat hepatocytes isolated by the collagenase perfusion method. 125I activity of cells after incubation with 125I-IOP (1.0-100 microM) was used as a measure of uptake. At each IOP concentration uptake was linear for the first 45 s. The initial uptake velocity was directly proportional to IOP concentration and was nonsaturable up to 100 microM. The calculated uptake rate constant was 0.67 nmol . mg prot-1 . min-1 . microM-1. Uptake was only slightly reduced when the incubation was performed at 4 degrees C and was independent of sodium concentration. Albumin in the medium reduced IOP uptake. Uptake, however, was always greater than that predicted from the unbound IOP concentration alone. The data indicate that the hepatocyte uptake of IOP occurs by both a passive process and a saturable process. The saturable uptake component depends on an albumin-IOP-hepatocyte interaction. The influence of albumin on uptake occurs possibly by an undefined specific cell surface phenomenon of albumin that promotes uptake of IOP or by enhancement of the diffusibility of IOP across the unstirred layer.

Theophylline, glucagon, and SQ-20009 induce a choleresis in the dog characterized by a proportionate increase in erythritol clearance and bile flow, no increase in bile salt excretion, and by an isosmotic solution of similar electrolyte composition. The increment in bile appears to originate at the canaliculus in response to increased cyclic-AMP.

The hepatic excretion of radiographic contrast materials has a major impact on the composition and volume of bile. One obvious effect is the presence of the contrast agent in bile at a concentration that is determined by the rate of hepatic excretion, the rate of basal bile flow, and the rate of bile flow induced by the biliary excretion of the contrast agent. The magnitude of the choleretic response associated with the biliary transfer of contrast materials varies over a wide range. Iopanoic acid does not increase bile flow, whole RCK-136, an experimental contrast material that is similar to iopanoic acid chemically (both are triiodophenyl alkanoates), is a potent choleretic, generating 44 microliter of bile for each mumol excreted into bile. In distinction, the contrast materials in another chemical class, the dimers of triiodobenzoic acid, increase bile flow, but over a narrow range (20-25 microliter/mumol). The changes in bile flow and composition accompanying the administration of iodoxamate, one of the compounds of the dimer type, were compared to the choleresis induced by taurocholate. The additional bile flow was canalicular in origin in both instances, but the electrolyte composition of the bile was different. Bicarbonate concentration in the iodoxamate-induced increment of bile was nearly twice the concentration of bicarbonate in bile stimulated by taurocholate (52.3 and 25.3 mEq/1, respectively). This suggests a canalicular mechanism for iodoxamate-stimulated bicarbonate entry into the bile. The characteristics of bile induced by iodoxamate were also compared to bile associated with a variety of other choleretic agents, including diethyl maleate, DBcAMP, SC2644, and secretin. Only SC2644 stimulated canalicular bile flow with a high bicarbonate concentration similar to iodoxamate.

The parameters which are important in causing changes in the T1 and T2 proton magnetic relaxation times of dogs bile were investigated. Three factors were found to be important in causing relaxation in bile: (i) total bile salt concentration; (ii) total protein concentration, and (iii) viscosity. The T1 and T2 values of hepatic and gallbladder biles were found to be independent of specific gravity, osmolarity and electrolyte concentrations. In vitro experiments were conducted with taurocholic acid, bovine serum albumin and porcine stomach mucin to examine the effects of intermolecular interactions on proton relaxation. Relative to each of the molecules alone, various combinations of the bile salt and proteins exhibit relaxation rates of 20 to 60% below theoretically expected values. This influence of in vitro molecular interactions on T1 and T2 is also likely to occur in hepatic and gallbladder biles in vivo. Thus, the effects of complex intermolecular interactions associated with the gallbladder microenvironment complicate but likely will not preclude direct assessment of physiologic data with magnetic resonance imaging.

Uptake of iopanoic acid (IOP) and iopanoate glucuronide (IOP-G) was studied in 3-day primary cultures of rat hepatocytes isolated by the collagenase perfusion method. 125I activity of cells after incubation with 125I-IOP (10-100 microM) and 125I-IOP-G (10-100 microM) was used as a measure of uptake. At each concentration, uptake was linear for the first 45 sec. In the absence of albumin, the initial uptake velocity was directly proportional to the concentration or IOP or IOP-G and was nonsaturable up to 100 microM. The calculated uptake rate constants for IOP and for IOP-G were 0.059 and 0.048 nmole/(mg protein X min X microM), respectively. IOP uptake was not inhibited by sodium taurocholate nor by the contrast agents iodipamide, ipodate, and iopronic acid. The data indicate that the enhancement of IOP excretion by bile salts noted in vivo does not occur at the uptake step and that the hepatic uptake of both IOP and IOP-G in the absence of albumin is limited by diffusion.