Rush B, Merritt M V, Kaluzny M, Van Schoick T, Brunden M N, Ruwart M
Prostaglandins. 1986 Sep;32(3):439-55. doi: 10.1016/0090-6980(86)90011-0.
We have previously demonstrated the partial protection of the rat liver by 16,16-dmPGE2 (DMPG) against a number of hepatotoxins including carbon tetrachloride (CCl4). However, it has not been determined whether hepatoprotection by DMPG represents a true "cytoprotective" action or if merely accomplished through inhibition of CCl4 metabolism to reactive, toxic trichoromethyl (CCl3.) free radicals. This report details a series of experiments in which the effects of DMPG on CCl4 metabolism was evaluated in the rat. These data indicate that pretreatment with DMPG may reduce the hepatic concentration of the toxic CCl3. free radicals in CCl4 poisoned rats. Evidence is presented which suggests that this reduction in binding may have been due to a decrease in the rate of CCl4 metabolism. However, DMPG did not affect the hepatic concentration of total microsomal cytochrome P450, the necessary enzyme in this metabolic process. On the other hand, free radical spin trapping experiments indicate that the rate of free radical formation from CCl4 was slowed by treatment. Also, indirect evidence suggests that the metabolism of another cytochrome P450 substrate, phenobarbital, was slowed in DMPG treated rats. We conclude that the rate of CCl4 metabolism may be reduced by pretreatment with DMPG. Furthermore, some measure of hepatic protection might be expected to occur as a result of the reduction in the rate of CCl4 metabolism. However, we are unable to determine if this action was solely responsible for the observed hepatic protection.
我们之前已经证明，16,16 - 二甲基前列腺素E2（DMPG）对包括四氯化碳（CCl4）在内的多种肝毒素具有部分保护大鼠肝脏的作用。然而，尚未确定DMPG的肝保护作用是代表真正的“细胞保护”作用，还是仅仅通过抑制CCl4代谢为具有反应性的有毒三氯甲基（CCl3·）自由基来实现。本报告详细介绍了一系列实验，其中评估了DMPG对大鼠CCl4代谢的影响。这些数据表明，用DMPG预处理可能会降低CCl4中毒大鼠肝脏中有毒CCl3·自由基的浓度。有证据表明，这种结合的减少可能是由于CCl4代谢速率的降低。然而，DMPG并不影响总微粒体细胞色素P450的肝脏浓度，而细胞色素P450是这一代谢过程中必需的酶。另一方面，自由基自旋捕获实验表明，处理后CCl4产生自由基的速率减慢。此外，间接证据表明，在DMPG处理的大鼠中，另一种细胞色素P450底物苯巴比妥的代谢也减慢。我们得出结论，用DMPG预处理可能会降低CCl4的代谢速率。此外，由于CCl4代谢速率的降低，可能会预期出现某种程度的肝脏保护作用。然而，我们无法确定这种作用是否是观察到的肝脏保护的唯一原因。
