Differing effects of the inhibition of poly(ADP-ribose) polymerase on the course of oxidative cell injury in hepatocytes and fibroblasts.
Differing effects of the inhibition of poly(ADP-ribose) polymerase on the course of oxidative cell injury in hepatocytes and fibroblasts.
复制标题
抑制聚（ADP-核糖）聚合酶对肝细胞和成纤维细胞氧化细胞损伤过程的不同影响。
DOI：
10.1016/0006-2952(93)90525-2
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发表时间：
1993
影响因子：
5.8
通讯作者：
Farber,JL
中科院分区：
文献类型：
--
作者：
Yamamoto,K;Tsukidate,K;Farber,JL
本文研究了两种聚ADP核糖聚合酶抑制剂3-氨基苯甲酰胺（阿坝）和苯甲酰胺（BA）对L929小鼠成纤维细胞和原代培养的大鼠肝细胞的氧化杀伤作用。叔丁基过氧化氢（TBHP）对L929细胞的杀伤作用有两种机制，一种对抗氧化剂N，N′-二苯基苯二胺（DPPD）敏感，另一种不敏感。通过任一机制的细胞杀伤被三价铁螯合剂去铁胺阻止。阿坝和B A阻止了在DPPD存在下发生的对L929细胞的杀伤，但在没有DPPD的情况下不能。阿坝和BA对聚ADP-核糖聚合酶的抑制率达85%。保护是伴随着节省的NAD和ATP的耗尽，但有没有影响的阿坝或BA上的铁依赖性外观的单链断裂的DNA。通过用2-脱氧葡萄糖和叠氮化钠处理成纤维细胞来消耗ATP不会导致任何活力丧失。H2 O2同样通过依赖于三价铁来源的机制杀死L929细胞。DPPD对细胞的杀伤作用不明显，阿坝和BA对DPPD的存在和不存在都有保护作用。H2 O2引起的单链断裂的外观，防止由去铁胺，但同样不是由阿坝或BA。阿坝和去铁胺减少，但没有阻止，NAD和ATP的耗尽发生与H2 O2。与培养的肝细胞，阿坝和BA抑制聚（ADP-核糖）聚合酶的浓度是没有影响的细胞杀伤的程度或NAD的耗尽发生与TBHP，H2 O2，或甲萘醌。这些数据表明，氧化性DNA损伤和致死性损伤的发生之间的关系是非常不同的两种类型的细胞。在成纤维细胞中，DNA单链断裂的出现伴随着NAD和ATP的耗尽，随后伴随着细胞的死亡。这些事件是由聚（ADP-核糖）聚合酶的活性介导的，因为抑制该酶可以阻止其发展。在肝细胞中，聚（ADP-核糖）聚合酶的抑制对细胞的氧化死亡没有影响。
The effects of the two inhibitors of poly(ADP-ribose) polymerase, 3-aminobenzamide (ABA) and benzamide (BA), on the oxidative killing of L929 mouse fibroblasts and primary cultures of rat hepatocytes were studied. The killing of L929 cells bytert-butyl hydroperoxide (TBHP) occurred by two mechanisms, one sensitive and the other insensitive to the antioxidantN,N′-diphenylphenylene diamine (DPPD). Cell killing by either mechanism was prevented by the ferric iron chelator deferoxamine. ABA and B A prevented the killing of L929 cells that occurred in the presence, but not in the absence, of DPPD. ABA and BA inhibited the activity of poly(ADP-ribose) polymerase by 85%. Protection was accompanied by the sparing of the depletion of both NAD and ATP, but there was no effect of either ABA or BA on the iron-dependent appearance of single-strand breaks in DNA. Depletion of ATP by treating the fibroblasts with 2-deoxyglucose and sodium azide did not result in any loss of viability. H2O2similarly killed the L929 cells by a mechanism that depended on a source of ferric iron. However, DPPD had no effect on the cell killing, and ABA and BA completely protected the cells in the presence or absence of DPPD. H2O2caused the appearance of single-strand breaks that were prevented by deferoxamine, but again not by ABA or BA. ABA and deferoxamine reduced, but did not prevent, the depletion of both NAD and ATP occurring with H2O2. With the cultured hepatocytes, ABA and BA inhibited poly(ADP-ribose) polymerase at concentrations that were without effect on either the extent of cell killing or the depletion of NAD occurring with either TBHP, H2O2, or menadione. These data indicate that the relationship between oxidative DNA damage and the genesis of lethal injury is very different in the two types of cells. In the fibroblasts, the appearance of single strand breaks in DNA was accompanied by depletion of NAD and ATP and subsequently by the death of the cells. These events were mediated by the activity of poly(ADP-ribose) polymerase, as inhibition of the enzyme prevented their development. In the hepatocytes, inhibition of poly(ADP-ribose) polymerase was without effect on the oxidative death of the cells.