Dose-dependent conjugation of sulfobromophthalein and hepatic transit timein bile fistula rats - Role of the microtubule-dependent vesicle pathway

Sulfobromophthalein (BSP) is selectively taken up by the liver and secreted into the bile as unconjugated and conjugated forms. Our previous study dem onstrated that unconjugated BSP, but not conjugated BSP, caused the dissoci ation of biliary lipid secretion from that of bile acids, suggesting that t he hepatic BSP conjugation rate partly regulated biliary lipid secretion. T o evaluate the mechanisms through which biliary lipid secretion is regulate d by exogenous organic anions, we intravenously administered BSP to male Sp rague-Dawley rats at various doses either continuously or as a bolus. Then the relationship of the dose of BSP to its conjugation rate, hepatic transi t time, and biliary lipid secretion was determined. BSP decreased biliary s ecretion of cholesterol and phospholipids in a dose-dependent manner withou t affecting bile acid secretion. In contrast, the proportion of conjugated BSP in bile was associated with the dose. Although the serum clearance of B SP after bolus infusion was constant regardless of the dose administered (5 0 or 200 nmol/100 g), BSP secretion was delayed with increasing doses: unco njugated BSP was secreted predominantly in the early phase (0-15 min after bolus injection), and conjugated BSP was the predominant form in the late p hase (15-30 min). Pretreatment with colchicine reduced the conjugation rate and hepatic transit time of BSP, suggesting that the microtubule-dependent vesicle pathway plays a role in biliary excretion and conjugation of BSP. We conclude that biliary lipid secretion is influenced by organic anions wi th an affinity for bile acids such as BSP and that this effect is dependent upon the hepatic metabolic rate, i.e., conjugation rate. The hepatic trans it time also plays a key role in this process by influencing metabolism.