Cholestasis induced by sodium taurolithocholate in isolated hamster liver

Abstract

The mechanism of cholestasis (decreased bile flow) induced by taurolithocholate in the isolated perfused hamster liver was investigated. Taurocholate was infused to maintain bile acid output, and sulfobromophthalein (BSP) was administered to establish a BSP transport maximum in bile. The effects of taurolithocholate on bile flow and on the biliary secretion of BSP and bile acid anions were determined.A significant dose-response correlation was found between taurolithocholate and the degree of cholestasis. No significant hepatic morphologic alterations were observed. At low doses, cholestasis was reversible. A multiple regression equation was developed to validate the steroid dehydrogenase determination of total bile acids in bile that contained BSP. During cholestasis, output of bile acid was maintained by a significantly increased concentration of bile acid. Hepatic removal rate and transport maximum of BSP were significantly decreased, whereas BSP concentration, conjugation, and hepatic content were unaffected. The concentrating capacity for BSP in bile appeared to be the rate-limiting factor in BSP transport. Individual bile acids were determined by gas-liquid chromatography. Of the injected taurolithocholate, 40-50% was recovered in bile as lithocholic acid, 30% was converted to chenodeoxycholic acid, and only traces of lithocholic acid were detected in the perfusate after 4 hr. Cholic and chenodeoxycholic acids comprised 75-89%, and lithocholic acid comprised 11-25% of bile acids in bile after taurolithocholate injection; only traces of deoxycholic acid were seen. Small amounts of taurolithocholate sulfate were detected in bile by thinlayer chromatography. The outputs of sodium and potassium in bile were significantly diminished during cholestasis.A substantial fraction (75%) of basal bile flow in the isolated hamster liver was estimated to be independent of bile acid secretion. Cholestasis occurred after taurolithocholate, whereas bile acid secretion was maintained. The results indicate that the most likely mechanism for acute cholestasis induced by taurolithocholate in isolated hamster liver was interference with the bile acid-independent fraction of canalicular or ductular bile flow or both.