Graduate Thesis Or Dissertation
 

Impaired organic anion excretion and cholestasis caused by 1,3-bis-(2-chloroethyl)-1-nitrosourea (carmustine or BCNU) in rats

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  • Previous investigation showed that 20 mg/kg BCNU caused inhibition of sulfobromophthalein (BSP) excretion and inhibited bile salt independent bile flow (BSIF) in rats by 48 h after treatment (Hoyt, 1984). The present investigation demonstrated that BCNU inhibited the canalicular step in the excretion of BSP. This was indicated by the inhibition of maximal excretion of BSP, inhibition of the biliary excretion of the non-metabolized dye, indocyanine green and the lack of inhibition of the conjugation of BSP with glutathione. Canalicular effects were also suggested because BCNU-pretreatment inhibited the excretion of endogenous reduced glutathione and oxidized glutathione. The inhibition of BSP excretion by BCNU did not appear to result from increased hepatic content of reduced or oxidized glutathione because these materials fell to normal levels at 72 h after 20 mg/kg BCNU. BSP excretion was inhibited by this dosage for at least 96 h (Hoyt, 1984). Inhibition of BSP excretion was not due to accumulation of bile salts because their depletion had no effect on BSP excretion in BCNU-treated rats. Pretreatment of rats with pentobarbital sodium prevented BCNU-induced cholestasis and inhibition of BSP excretion. Pentobarbital may have stimulated BSIF, altered the response of the liver to BCNU, changed the amount and/or types of interactions of BCNU with liver or reduced the amount of BCNU reaching sites of action. Theophylline and glucagon infusions stimulated bile flow in BCNU-treated rats. These agents may have increased intracellular cyclic adenosine monophosphate (cAMP) content. The research of others indicates that cAMP may stimulate sodium-coupled chloride transport in epithelia. Therefore, this transport or hepatocellular cAMP may be depressed in BCNU-treated rats. Theophylline and glucagon may have stimulated bile flow so that the effect of BCNU on other systems was masked. Analysis of biliary bile salt composition demonstrated that there was no increase of the more hydrophobic, toxic bile salts. No action of BCNU is related to the hypothesized accumulation. The opposite trend, a shift to hydrophilic bile salts, was observed. This shift is observed in cholestasis caused by alpha-napthyl isothiocyanate, ethinyl estradiol and bile duct ligation, suggesting that it is a result of cholestasis.
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