Cholestasis and the interactions of sulfated glyco- and taurolithocholate with calcium

To elucidate possible mechanisms of the differential cholestatic effect of sulfated glyco- and taurolithocholate (SGLC and STLC) the interactions of these bile acids with calcium were studied both in vitro and in vivo. In vitro, SGLC was readily precipitated by Ca in physiological concentrations (less than 5 mM). It appeared that only micelles of SGLC were precipitated and that both the sulfate and the carboxylate anionic groups participated in Ca binding. Conjugation with taurine almost completely prevented this Ca-dependent precipitation. Intravenous infusion of SGLC (12 mumol/h) in unanesthetized rats with permanent biliary drainage induced cholestasis, which was preceded by the formation of a biliary Ca-SGLC precipitate, suggesting a causal relationship. Taurine conjugation prevented this biliary precipitation as well as cholestasis. Furthermore, we studied in vitro the binding of the sulfated bile acids to insoluble calcium phosphate, simulating interactions with Ca at the intestinal level. Compared with STLC, micellar SGLC was bound with much higher affinity. This high-affinity binding was probably due to the involvement of both the sulfate and the carboxylate group. This might also explain that the apparent critical micellar concentration of SGLC, in contrast to that of STLC, was extremely Ca dependent. The present findings indicate that 1) interaction with calcium might be responsible for the differential cholestatic properties of SGLC and STLC and 2) binding of sulfated lithocholic acid conjugates to insoluble calcium phosphate in the intestinal lumen is likely to prevent their accumulation in the enterohepatic circulation.