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 micromol/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.