Drug-induced cholestasis in the perfused rat liver and its reversal by tauroursodeoxycholate: an ultrastructural study.
Chlorpromazine at a concentration of 250 microM and estradiol-17 beta-D-glucuronide at 17.5 microM on infusion led to a sharp reduction in bile flow by the in vitro perfused rat liver. This was accompanied by fragmentation and a loss of canalicular microvilli, dilatation of canaliculi, and thickening of pericanalicular ectoplasm. Less prominent were the smooth endoplasmic reticulum dilatation, lysosomal lamination, and the appearance of amorphous bile in hepatocyte cytoplasm. The bile flow and electron microscopy appearance were restored to normal by infusion of tauroursodeoxycholate in a concentration of 5 mumols/min for the estradiol-17 beta-D-glucuronide-induced cholestasis and 1.5 mumol/min for the chlorpromazine-induced cholestasis. Changes in ultrastructure paralleled changes in bile flow. These observations demonstrate the feasibility of electron microscopy studies on the perfused liver, and the rapidity with which cholestatic changes appear.
Abernathy
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Office of Water, United States Environmental Protection Agency, Washington, DC 20406.
Zimmerman
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Ishak
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Utili
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Gillespie
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D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002746:Chlorpromazine / Q000633:toxicity*; D002779:Cholestasis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D008854:Microscopy, Electron; D010477:Perfusion; D051381:Rats; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013997:Time Factors
C025482:estradiol-3-glucuronide; D004958:Estradiol; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D002746:Chlorpromazine