Role of perivenous hepatocytes in taurolithocholate-induced cholestasis in vivo

Abstract

The magnitude of cholestasis induced by taurolithocholic acid (TLCA) and its relationship with phase I metabolism were analyzed in rats treated with bromobenzene (BZ), a chemical that causes selective necrosis of perivenous (zone 3) hepatocytes. Forty-eight hours after BZ administration (600 mg/Kg bw), a single dose of 20 μmol/Kg bw of TLCA was injected. Bile was collected during 180 min and bile flow and total bile acid excretion rate were determined. Biliary bile acid composition was analyzed by gas–liquid chromatography-mass spectrometry. BZ administration did not affect the development of TLCA-induced cholestasis, but exacerbated the bile acid-induced decrease in bile flow during the period of recovery from cholestasis. Biliary excretion of total bile acids after TLCA injection relative to basal value was not effected by BZ. The analysis of bile acid composition in bile revealed that TLCA was partially converted to hyodeoxycholic and muricholic acids. The cumulative excretion of all exogenous bile acids and their contribution to the composition of the biliary bile acid pool were not substantially affected by zone 3 necrosis, suggesting that synthesis and secretion of hydroxylated derivatives of TLCA were maintained by zone 1 and 2 hepatocytes. The relative content of endogenous bile acids was not affected by BZ during TLCA-induced cholestasis. Thus, it seems unlikely that the exacerbation of the cholestasis in BZ-treated rats is due to different choleretic properties and/or toxicity of the bile acid pool.