Characterization of cholestasis induced by 1,3-bis-(2-chloroethyl)-1-nitrosourea in rats Public Deposited

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  • BCNU caused severe cholestasis in rats after a single intraperitoneal injection. The cholestasis was characterized by a selective reduction of the bile salt independent bile flow to 11% of control. Decreased food or water consumption by the treated rats apparently did not contribute to cholestasis. Measurements of plasma Na⁺ and K⁺ concentrations were consistent with current concepts regarding the role of Na⁺/K⁺ ATPase in the formation of bile salt independent bile flow. Nevertheless, the possibility that the permeability of water to the canalicular space may be reduced in treated rats remains to be evaluated. Although bile salt excretion rates were slightly reduced in treated rats during cholestasis, bile salt concentrations in bile were elevated. Therefore, bile salt excretion was limited by cholestasis, not by a defect in concentrative transport. This increase in biliary bile salt concentration and increases in bile:plasma osmolality ratios tend to discount a breakdown of the bile:plasma permeability barrier as a cause of cholestasis in BCNU treated rats. In contrast to the effect of BCNU on bile salt excretion, treated rats failed to concentrate the xenobiotic organic anion, sulfobromophthalein (BSP), in bile to a normal extent. This was evident prior to the onset of cholestasis and, therefore, may be reflective of the lesion that causes cholestasis. Because BSP excretion depends largely upon conjugation of the dye with glutathione (GSH), hepatic GSH and BSP metabolites in bile were monitored. BCNU caused an increase in hepatic GSH before its effects on BSP excretion and bile flow were evident. The effect on GSH may be a result of stimulated synthesis, inhibited enzymatic degradation, inhibited efflux from the hepatocyte, or a combination of these. In any case, the decreased BSP excretion was not due to a lack of substrate for conjugation. BCNU, besides inhibiting BSP excretion, produced a qualitative change in BSP metabolites found in bile. This effect may be due to an alteration of GSH-S-transferase activity in treated rats. However, decreased canalicular excretion or bisolateral uptake may acount for the results.
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