VASOPRESSIN REDUCES TAUROCHENODEOXYCHOLATE-INDUCED HEPATOTOXICITY BY LOWERING THE HEPATOCYTE TAUROCHENODEOXYCHOLATE CONTENT

Background/Aims: Vasopressin has been reported to reduce bile how, but its effects on bile acid secretion and bile acid-related hepatotoxici ty are still unclear, We therefore investigated the influence of vasop ressin on the hepatotoxicity and biliary excretion of taurochenodeoxyc holic acid in primary cultured rat hepatocytes and isolated perfused r at liver models. Methods/Results: 1) Addition of vasopressin to hepato cyte cultures significantly decreased lactate dehydrogenase release as compared to cultures exposed to 1 mM taurochenodeoxycholic acid alone , and also reduced intracellular taurochenodeoxycholic acid content fr om 19.3+/-2.2 to 13.0+/-1.6 nmol/mg protein, After 30 min of preincuba tion with 1 mM taurochenodeoxycholic acid, rinsing and reculture of he patocytes in bile acid-free medium resulted in gradual decrease in the intracellular level of the bile acid, and addition of vasopressin (10 (-9) M) to the reculture medium accelerated this process. 2) Superimpo sition of vasopressin (330 pmol/l) for 10 min on taurochenodeoxycholic acid infusion (1.0 mu mol/min: 25 mu mol/1) caused a rapid increase i n bile flow and biliary excretion of taurochenodeoxycholic acid (697+/ -42 vs 584+/-27 nmol/10 min per g liver) from perfused rat livers, and significantly reduced lactate dehydrogenase release, 3) Superimpositi on of the PKC blocker H-7 (5 mu mol/l) on taurochenodeoxycholic acid i nfusion (1.0 mu mol/min: 25 mu mol/l) caused a gradual increase in bil e flow and biliary excretion of taurochenodeoxycholic acid. Furthermor e, an additional infusion of vasopressin (100 pmol/l) for 10 min in th e presence of H-7 produced a greater increase in bile flow and biliary excretion of taurochenodeoxycholic acid as compared with H-7 alone (7 54+/-71 vs, 657+/-26 nmol/g liver), 4) Continuous infusion of vasopres sin (330 pmol/l) significantly increased the late peak (10-50 min) of horseradish peroxidase excretion from perfused livers (from 8.48+/-1.0 2 to 21.7+/-6.02 ng/g liver), Conclusions: These findings suggest that vasopressin exerts a protective effect against taurochenodeoxycholic acid-induced hepatotoxicity by stimulating the secretion of this bile acid via intracellular vesicular transport systems.