Lindstrom T D, Hanssen B R, Bendele A M
Department of Drug Metabolism, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
Mol Pharmacol. 1990 Dec;38(6):829-35.
Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation. Serum alanine transaminase and aspartate transaminase concentrations were increased by reperfusion of previously ischemic tissue. Reperfusion of the previously ischemic lobe for 18 hr was associated with a greater loss of cytochromes P-450 and b5, cytochrome c reductase, and ethylmorphine demethylation than reperfusion for 1 hr. The total decrease in cytochrome P-450 and b5 content was equal to the decrease in total microsomal heme content, although cytochrome P-450 decreased more than cytochrome b5. Ethoxyresorufin deethylation by hepatic microsomes from 3-methylcholanthrene-treated rats was decreased by ischemia-reperfusion; however, pentoxyresorufin dealkylation by hepatic microsomes from phenobarbital-treated rats was not, suggesting specific cytochrome P-450 isozyme loss. In vitro NADPH-dependent lipid peroxidation in hepatic microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats resulted in a selective decrease of ethoxyresorufin but not pentoxyresorufin dealkylation, similar to that observed in livers subjected to ischemia-reperfusion in vivo. These data suggest that cytochrome P-450, ethylmorphine demethylation, and ethoxyresorufin deethylation are more susceptible to ischemia-reperfusion injury than cytochrome b5 or pentoxyresorufin dealkylation.
通过结扎大鼠左肝叶在体内诱导长达2小时的肝缺血，对细胞色素P - 450、细胞色素c还原酶或肝叶组织学没有影响；然而，细胞色素b5随缺血时间延长而增加。缺血2小时后，乙基吗啡脱甲基作用降低了35%。先前缺血长达2小时的组织再灌注与明显的坏死以及细胞色素P - 450、细胞色素b5、细胞色素c还原酶和乙基吗啡脱甲基作用的降低有关。先前缺血组织的再灌注使血清丙氨酸转氨酶和天冬氨酸转氨酶浓度升高。先前缺血的肝叶再灌注18小时比再灌注1小时导致细胞色素P - 450和b5、细胞色素c还原酶以及乙基吗啡脱甲基作用的损失更大。细胞色素P - 450和b5含量的总下降等于微粒体总血红素含量的下降，尽管细胞色素P - 450的下降比细胞色素b5更多。3 -甲基胆蒽处理的大鼠肝微粒体的乙氧异吩唑酮脱乙基作用因缺血 - 再灌注而降低；然而，苯巴比妥处理的大鼠肝微粒体的戊氧异吩唑酮脱烷基作用则未受影响，这表明特定的细胞色素P - 450同工酶丧失。来自对照、苯巴比妥和3 -甲基胆蒽处理的大鼠的肝微粒体中，体外NADPH依赖性脂质过氧化导致乙氧异吩唑酮脱乙基作用选择性降低，但戊氧异吩唑酮脱烷基作用未受影响，这与体内经历缺血 - 再灌注的肝脏中观察到的情况相似。这些数据表明，细胞色素P - 450、乙基吗啡脱甲基作用和乙氧异吩唑酮脱乙基作用比细胞色素b5或戊氧异吩唑酮脱烷基作用更容易受到缺血 - 再灌注损伤。
