Nature of bile acid maximum secretory rate in the rat

Abstract

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.

Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: A study in vivo and in isolated hepatocyte couplets

“…TUDC was chosen because of its extremely low toxicity, in contrast to other naturally occurring bile salts, whose apparent maximum transport is largely determined by their cytotoxicity rather than by saturation of their canalicular transport system. 36 The SRM of TUDC was assessed by infusing the bile salt intravenously, dissolved in 2% BSA in saline, at stepwise-increasing rates (2.0, 2.5, 5.0, 6.5, 12.0, and 16.0 mol/min/100 g body wt). Each infusion rate was maintained for 20 minutes, and bile samples were collected every 10 minutes for 120 minutes.…”

“…SRM was calculated as the mean of the 3 highest, consecutive secretory rates recorded over the whole infusion period. 36 The BSIF was estimated in these animals by the conventional extrapolation to zero bile salt output of the regression line between the bile flow and the bile salt output, as stimulated by TUDC infusion. 37 Hepatic Handling of BSP.…”

Effects of high taurocholate load on activities of hepatic alcohol metabolizing enzymes

“…We have earlier reported the leakage of ADH into the blood stream and activity changes of the other alcohol metabolizing enzymes in cholestasis induced by BDO in rats (Kwak et al, 1988). The cytotoxicity of bile acid in vivo was further extended by examining the leakage of ADH and other alcohol metabolizing enzymes into the blood stream as a cytotoxic parameter of the liver from CCF rats and BDO during 2 days period under the influence of the hydrophobic TCA (7α-planar) or hydrophilic TUDCA (7β-nonplanar) (Hardison et al, 1981). The activity of ADH in the serum increased significantly soon after BDO or CCF (groups 3 and 6) over the levels of those activities from each control (groups 1 and 2), although the cytosolic ADH activity levels remained about the same in either or both models.…”

“…Bile acids cytotoxicity is thought to be dependent on their detergent property (Hardison et al, 1981;Kitani et al, 1986;Morgan et al, 1998) or lipid-solubilizing properties (Ogawa et al, 1990). At concentration near the critical micellar concentration, or at high perfusion rate, bile salts are capable of solubilizing cell membrane components (Morgan et al, 1998) leading to cell lysis (Drew and Priestly, 1963).…”

Regulation of hepatocellular bile salt secretion: Who shoots the messengers

“…The effects of nocodazole could tocyte toxicity, and bile flow trickles to a halt. 1 Exogenously administered ursodeoxycholic acid stimulates bile flow and be largely reversed by replacing the culture medium with nocodazole-free medium 2 hours before experimentation. The protects hepatocytes from damage by other bile salts, yet is so hydrophilic as to have virtually no hepatotoxic side ef-addition of DBcAMP to nocodazole-treated cells had a partial stimulatory effect, suggesting that a pool of vesicles was still fects.…”