Intrahepatic cholestasis induced by allo monohydroxy bile acid in rats

Abstract

Little is known about the biologic effect of allo bile acids on the liver. Since the monohydroxy-5β-cholanic acids are known to induce a well-characterized intrahepatic cholestasis, the effects of 3β-hydroxy-5α-cholanic acid was tested in these studies. The bile ducts of 18 male Wistar rats were cannulated, and bile was collected for 2 h. The rats were then divided into three groups: The first group was injected i.v. with 6 μmol/100 g body weight of 3β-hydroxy-5α-cholanic acid in normal saline containing 7.5% albumin. The second group was injected with a similar concentration of the sulfate ester. The third group (control animals) received only albumin-saline solution. Bile was collected for 2 h at 15, 30, 60, and 120 min. Bile volume and biliary lipids were measured. The livers were biopsed at 30 min after injection and at the end of the experiment for examination by electron microscopy, and a morphometric analysis was performed. The 3β-hydroxy-5α-cholanic acid and its sulfate ester significantly reduced bile flow, bile salt, cholesterol, and phospholipid secretion in the 1st hour. However there was a tendency for improvement of these parameters in the 2nd hour after injection. The reduction in bile flow was dose dependent. At 30 min after injection, marked changes were observed at the canalicular pole of the hepatocytes. The canaliculi showed dilatation and partial or total loss of microvilli. Pericanalicular diverticuli originating from the plasma membrane intruded into the underlying cytoplasm. Amorphous material and clusters of microfilaments were seen around the pericanalicular vacuoles. At 2 h, the hepatocytes showed the same changes described at 30 min but to a lesser degree. These data suggest that (a) allomonohydroxy bile acids have a greater cholestatic potential than 5β-analogues (four times the concentration of 5β-analogue was required to produce the same degree of cholestasis); (b) the sulfation does not protect against the cholestatic effect of allomonohydroxy bile acids; and (c) the mechanism of allo-monohydroxy bile acid cholestasis involves an early morphologic change in the bile canalicular membrane.