Lithocholate-3-O-glucuronide-induced cholestasis. A study with congenital hyperbilirubinemic rats and effects of ursodeoxycholate conjugates.
The mechanism of lithocholate-3-O-glucuronide-induced cholestasis is unknown. In this study, we investigated the cholestatic effects of this agent in a congenital hyperbilirubinemic rat, EHBR. We also studied the effects of ursodeoxycholate-3-O-glucuronide and tauroursodeoxycholate on lithocholate-3-O-glucuronide-induced cholestasis in rats. Lithocholate-3-O-glucuronide, administered at the rate of 0.1 mumol/min/100 g for 40 min, a cholestatic dose in control rats, failed to cause cholestasis in EHBR, and biliary lithocholate-3-O-glucuronide excretion was delayed. Biliary concentrations of this agent did not correlate with the severity of cholestasis. Both tauroursodeoxycholate and ursodeoxycholate-3-O-glucuronide, infused at the rate of 0.2 mumol/min/100 g for 120 min, completely inhibited cholestasis induced by lithocholate-3-O-glucuronide administered at the rate of 0.1 mumol/min/100 g for 40 min. Only tauroursodeoxycholate enhanced biliary lithocholate-3-O-glucuronide excretion. These findings indicate that lithocholate-3-O-glucuronide-induced cholestasis is induced by damage at the level of the bile canalicular membrane. Ursodeoxycholate-3-O-glucuronide inhibits this cholestasis, possibly by inhibiting the access of lithocholate-3-O-glucuronide to the bile canalicular membrane.
Takikawa
H
H
Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.
Minagawa
K
K
Sano
N
N
Yamanaka
M
M
D000818:Animals; D001646:Bile / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced* / Q000503:physiopathology; D005965:Glucuronates; D006933:Hyperbilirubinemia, Hereditary / Q000150:complications* / Q000503:physiopathology; D008095:Lithocholic Acid; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D005965:Glucuronates; C076256:ursodeoxycholic acid-3-O-glucuronide; D013655:Taurochenodeoxycholic Acid; D008095:Lithocholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid; C041558:lithocholate 3-O-glucuronide