In vivo and in vitro studies on the protective effects of 9 beta-methylcarbacyclin, a stable prostacyclin analogue, in galactosamine-induced hepatocellular damage.
Early treatment with prostacyclin (PGI2) was previously shown to reduce mortality in the galactosamine model of acute hepatic failure in the rat, with a decreased release of hepatic cytosolic and lysosomal enzymes. In this study, 9 beta-methylcarbacyclin, a chemically stable analogue of PGI2, had similar protective effects to PGI2 in vivo but required approximately 100-fold higher concentrations (2 mg kg-1). These effects were only obtained when 9 beta-methylcarbacyclin was given early (0 to 6 h post-galactosamine) but not later (24 to 30 h). In isolated rat hepatocytes in vitro galactosamine up to a concentration of 100 mM caused a dose-dependent inhibition of L-[U-14C] leucine incorporation into protein and increase in the release of the cytoplasmic enzyme lactate dehydrogenase. Studies on the short-term effects of 9 beta-methylcarbacyclin using isolated hepatocytes treated with galactosamine (5 mM) showed that this agent, at an optimum concentration of 30 ng ml-1, was capable of significantly reducing the inhibition of protein synthesis caused by galactosamine but did not alter the rate of release of lactate dehydrogenase. The results demonstrate that the protective effects of 9 beta-methylcarbacyclin occur early in the time course of galactosamine action, and include direct effects on the hepatocytes.
Gove
C D
CD
Liver Unit, King's College Hospital, School of Medicine and Dentistry, Denmark Hill, London, UK.
Hughes
R D
RD
Kmiec
Z
Z
Noda
Y
Y
Williams
R
R
D000818:Animals; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D005688:Galactosamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D051381:Rats
D011465:Prostaglandins, Synthetic; D005688:Galactosamine; D011464:Epoprostenol; D007770:L-Lactate Dehydrogenase; D007930:Leucine; C045329:ciprostene