Different protective effects of tauroursodeoxycholate, ursodeoxycholate, and 23-methyl-ursodeoxycholate against taurolithocholate-induced cholestasis

Abstract

The coinfusion of tauroursodeoxycholate (TUDC) prevents taurolithocholate (TLC) -induced cholestasis. 23-Methyl-ursodeoxycholate (MUDC) is a side-chain derivative of ursodeoxycholate (UDC). If conjugation with taurine is important for the protective effect of UDC, the MUDC may not be as able as TUDC to prevent TLC-induced cholestasis since it is poorly amidated by the liver. To answer this question, isolated livers of adult Sprague-Dawley rats were coinfused with MUDC (UDC, TUDC) and TLC. After 15 min, inflow rates of the bile acids were doubled. In further experiments taurine in excess was added to the coinfused bile acids. The uptake of bile acids was >90% in all groups, irrespective of whether they were perfused alone or in combination. Single perfusion of TLC caused a rapid decrease in bile flow. UDC and MUDC were hypercholeretic; TUDC moderately choleretic. During coinfusion experiments, TUDC not only completely abolished cholestasis but in addition increased bile flow and biliary bile acid secretion. UDC did prevent TLC cholestasis at the lower inflow rates. At high inflow rates, bile flow decreased significantly. Addition of taurine to this bile acid combination did not significantly improve the anticholestatic effect of UDC. At low and high infusion rates of MUDC, cholestasis induced by TLC was reduced very little. Cumulative bile flow over 30 min fell by approximately 70% as compared to that of singly perfused MUDC. Addition of taurine to the coinfused MUDC/TLC slightly, but less significantly, improved the anticholestatic effect of MUDC. Since MUDC is by far less protective than UDC (and TUDC) despite similar physiochemical properties, it is concluded that taurine conjugation of UDC seems to be a prerequisite to prevent TLC-induced cholestasis. The results imply that treatment of cholestatic liver diseases with taurine-conjugated UDC might be more appropriate than with unconjugated UDC in cases where taurine conjugation is defective or where taurine depletion has occurred.

Transport of fluorescent bile acids by the isolated perfused rat liver: Kinetics, sequestration, and mobilization

“…The mobilization of sequestered fluorescent bile acids by the coinfusion of conjugated bile acids is analogous to the mobilization of cholestatic bile acids such as chenodeoxycholyl-taurine or lithocholyltaurine (taurolithocholate) by the coinfusion of bile acids such as UDC-taurine. [44][45][46][47] If the sequestered fluorescent bile acids are surrogates for endogenous cytotoxic bile acids, our results suggest that the cytoprotective effect of UDCA observed, for example, with isolated hepatocytes (see Benz 48 ), can be explained by UDCA preventing sequestration of cytotoxic bile acids in organelles. Such a mechanism of cytoprotection might be termed ''organelle blockade.''…”

Tauroursodeoxycholate and S–Adenosyl–L–Methionine Exert An Additive Ameliorating Effect on Taurolithocholate–Induced Cholestasis: A Study in Isolated Rat Hepatocyte Couplets

“…Initial suggestions that UDCA may replace the more toxic, endogenous bile acids 26 or inhibit their intestinal uptake has not been confirmed in further studies, 27 and the choleretic potency of UDCA seems to play only a minor role in its hepatoprotective action. 25 TUDCA has also been shown to elicit a protective effect against hydrophobic bile-acid-induced cholestasis 13,[28][29][30] and in cholestatic patients, 31 although the mechanisms involved in this protection are not yet clear. Circumstantial evidence has been provided that TUDCA prevented actin cytoskeletal derangement.…”

Tauroursodeoxycholic Acid Enhances the Pre‐Implantation Embryo Development by Reducing Apoptosis in Pigs

“…2001) and choleretic effects on hepatocytes (Milkiewicz et al. 2001) by increasing bile flow and biliary acid secretion (Baumgartner et al. 1996) and hepatocellular vesicular exocytosis (Beuers et al.…”

“…UDCA and TUDCA can also directly inhibit the production of reactive oxygen species, eliminate the transmembrane potential and disrupt the outer mitochondrial membrane (Castro et al 2004). These compounds produce not only anti-apoptotic effects (Rodrigues et al 1998(Rodrigues et al , 1999, but also cytoprotective effects (Tsukahara et al 1993;Ejiri et al 2001) and choleretic effects on hepatocytes (Milkiewicz et al 2001) by increasing bile flow and biliary acid secretion (Baumgartner et al 1996) and hepatocellular vesicular exocytosis (Beuers et al 1993).…”