We studied the determinants of maximum bile acid secretory rate (SRm) in the rat. The choledochocaval fistula rat model manifested a bile acid secretory rate far in excess of the SRm previously reported for taurocholate in this species. We studied the ability of various bile acid solutions to maintain the high secretion rate in this model. Whole-rat bile, but not taurocholate in 2% albumin nor rat bile with bile acid content over 90% taurocholate, maintained secretion rate. We concluded that the mixture of bile acids in rat bile was the most important determinant of the high secretion rate and that the high rate was not due to a peculiarity of the model itself nor to the infusion of biliary lipids together with bile acids. Conventional determination of the SRm in the bile fistula rat confirmed this impression, with the least toxic bile acids manifesting the highest SRm. During infusion of taurocholate beyond the SRm, bile flow and bile acid secretion rate fell. This was accompanied only by scattered focal necrosis of single liver cells or of small aggregates of cells and not by any diffuse subcellular morphological change. We believe the maximum bile acid secretory rate is determined by toxicity of a specific bile acid for the secretory mechanism rather than by a limitation in transport receptor number as is usual with substances manifesting classical transport maxima. The high SRm of the 7 beta-hydroxy bile acid, ursodeoxycholic acid, is probably related to its very low toxicity. The high SRm in the choledochocaval fistula rat is probably related to the presence of 7 beta-hydroxy muricholic acids in the bile of this species.

The role of bile acids in the biliary secretion of alkaline phosphatase was studied. Rats with external bile fistulae were drained for 4 hr. After 2 hr, bile acid secretion fell progressively. Alkaline phosphatase secretion also decreased progressively during the period of drainage, suggesting that secretion of the two components was related. Each rat was then given an i.v. infusion of the taurine conjugate of either cholate, chenodeoxycholate, or ursodeoxycholate. Alkaline phosphatase secretion increased in a dose-dependent manner as bile acid secretion was varied over and beyond the physiologic range. Each bile acid affected alkaline phosphatase secretion differently: given at 0.5 v o l e s per min per 100 gm, tauroursodeoxycholate caused a %fold, taurocholate a 14-fold, and taurochenodeoxycholate a 75-fold increase in enzyme secretion. To determine if these findings might represent elution of canalicular enzyme by bile acids, isolated liver surface membranes were incubated with the bile acids. Like the findings in uiuo, taurochenodeoxycholate was strongest and tauroursodeoxycholate weakest in removing alkaline phosphatase from the membrane. Differential centrifugation of liver surface membranes after exposure to bile acids and ultracentrifugation of bile showed that more than half of the enzyme released by the action of bile acids did not sediment at 100,000 g and, thus, could be considered soluble. These results document bile acid-dependent secretion of alkaline phosphatase in rat bile and suggest that the process involves solubilization of both membrane fragments and free enzyme from membranes lining the biliary space.

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