Acute cholestasis induced by lithocholic acid in the rat. A freeze-fracture replica and thin section study.
Sodium lithocholate (LCA) was continuously infused intravenously (0.1 or 0.2 mumole per minute per 100 gm. body weight) in Wistar rats with a bile fistula for up to 4 hours. The higher dose induced complete cholestasis within 2 to 3 hours, whereas the low dose reduced the biliary output to less than 10 per cent of the preinfusion level by the 3rd hour. Ultrastructural changes which were primarily localized to the bile canaliculi and the pericanalicular region were seen 30 minutes after the onset of bile acid infusion. Dilation of the bile carnaliculi, loss of canalicular microvilli, prominence of the pericanalicular ectoplasm, and a characteristic lamellar transformation of the canalicular membrane developed, which became more prominent and widespread with progression of time. A freeze-fracture replica study revealed that the canalicular microvilli became transformed through widening and flattening into multilamellar foldings. Intramembranous granules of the canalicular membrane appeared to have become redistributed, being few or absent in the "transformed" regions. In addition, a sharply angulated, crystalline material was seen in occasional bile canaliculi. This material appeared as a negative image in thin sections, indicating its solubility in organic solvents which were used for dehydration. With the lower dose of LCA, subcellular changes were similar to, but less severe and which accompany an acute cholestasis induced by LCA is attributable to the accumulation of this compound in the bile canaliculus and its vicinity. LCA presumably causes an asymmetric perturbation in the molecular organization of the canalicular membrane which results in ultrastructural alterations and failure of fluid transport. In addition, precipitates of LCA appear to form in the bile canaliculi and may contribute to cholestasis.
D000818:Animals; D001646:Bile / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000648:ultrastructure*; D002779:Cholestasis / Q000139:chemically induced / Q000473:pathology*; D002793:Cholic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D005260:Female; D005614:Freeze Fracturing; D006056:Golgi Apparatus / Q000648:ultrastructure; D007263:Infusions, Parenteral; D008095:Lithocholic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure*; D008247:Lysosomes / Q000648:ultrastructure; D008854:Microscopy, Electron; D008867:Microtomy; D008930:Mitochondria, Liver / Q000648:ultrastructure; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects
D002793:Cholic Acids; D008095:Lithocholic Acid