Effect of phalloidin on cholestasis, hemodynamics, and microcirculation in isolated perfused rat liver.
In this study, the possible role of the hepatic microcirculation in phalloidin-induced cholestasis and hepatotoxicity was examined in isolated perfused rat livers (IPRL). Administration of a phalloidin bolus (1 mg/kg body weight) through the portal vein induced an immediate reduction of bile flow. In 16.9 minutes, bile flow was 50% lower than basal values. Portal pressure was only increased in 60 minutes after phalloidin injection and increased sharply from this time up to the end of perfusion (90 minutes). Under these conditions, phalloidin did not induce liver cell cytolysis, as assessed by aspartate transaminase (AST) and lactate dehydrogenase (LDH) release in the perfusate effluent. Under electron microscopy, hepatocytic vacuolization was mild 15 minutes after phalloidin administration but increased with time. At the end of perfusion, the hepatic architecture was markedly altered; erythrocyte accumulation was observed in both sinusoids and hepatocyte vacuoles. Evaluation by multiple indicator dilution curves showed that extravascular volume (EVV) was significantly affected by phalloidin. It was augmented in 30 minutes after phalloidin administration with values increasing gradually over time. Neither vascular nor cellular volume was altered. The hepatic swelling may be attributed to enlargement of the extravascular space of the liver. These results indicate that changes in the liver microcirculation are not the primary cause of phalloidin-induced cholestasis in the IPRL.
Barriault
C
C
Department of Pharmacology, Université de Montréal, Canada.
Petit
J L
JL
Gascon-Barré
M
M
Huet
P M
PM
Yousef
I M
IM
Tuchweber
B
B
D000818:Animals; D001646:Bile / Q000502:physiology; D001647:Bile Acids and Salts / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002779:Cholestasis / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008833:Microcirculation / Q000187:drug effects; D010477:Perfusion; D010590:Phalloidine / Q000494:pharmacology*; D011168:Portal System / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014022:Tissue Survival / Q000187:drug effects
D001647:Bile Acids and Salts; D010590:Phalloidine