Role of perivenous hepatocytes in taurolithocholate-induced cholestasis invivo

The magnitude of cholestasis induced by taurolithocholic acid (TLCA) and it s relationship with phase I metabolism were analyzed in rats treated with b romobenzene (BZ), a chemical that causes selective necrosis of perivenous ( zone 3) hepatocytes. Forty-eight hours after BZ administration (600 mg/Kg b w), a single dose of 20 mu mol/Kg bw of TLCA was injected. Bile was collect ed during 180 min and bile flow and total bile acid excretion rate were det ermined. Biliary bile acid composition was analyzed by gas-liquid chromatog raphy-mass spectrometry. BZ administration did not affect the development o f TLCA-induced cholestasis, but exacerbated the bile acid-induced decrease in bile flow during the period of recovery from cholestasis. Biliary excret ion of total bile acids after TLCA injection relative to basal value was no t effected by BZ. The analysis of bile acid composition in bile revealed th at 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 affec ted by zone 3 necrosis, suggesting that synthesis and secretion of hydroxyl ated derivatives of TLCA were maintained by zone 1 and 2 hepatocytes. The r elative 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 an d/or toxicity of the bile acid pool. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.