Gove C D, Hughes R D, Kmiec Z, Noda Y, Williams R
Liver Unit, King's College Hospital, School of Medicine and Dentistry, Denmark Hill, London, UK.
Prostaglandins Leukot Essent Fatty Acids. 1990 May;40(1):73-7. doi: 10.1016/0952-3278(90)90120-a.
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.
先前的研究表明，前列环素（PGI2）早期治疗可降低大鼠急性肝衰竭半乳糖胺模型的死亡率，并减少肝细胞溶质和溶酶体酶的释放。在本研究中，9β-甲基前列环素是PGI2的化学稳定类似物，在体内具有与PGI2相似的保护作用，但所需浓度约高100倍（2 mg·kg-1）。这些作用只有在早期（半乳糖胺给药后0至6小时）给予9β-甲基前列环素时才能获得，而在后期（24至30小时）则不能。在体外分离的大鼠肝细胞中，高达100 mM浓度的半乳糖胺可导致L-[U-14C]亮氨酸掺入蛋白质的剂量依赖性抑制，并增加细胞质酶乳酸脱氢酶的释放。使用经半乳糖胺（5 mM）处理的分离肝细胞对9β-甲基前列环素的短期作用进行的研究表明，该药物在最佳浓度30 ng·ml-1时，能够显著降低半乳糖胺引起的蛋白质合成抑制，但不会改变乳酸脱氢酶的释放速率。结果表明，9β-甲基前列环素的保护作用发生在半乳糖胺作用过程的早期，并且包括对肝细胞的直接作用。
