Oxidative cell injury in the killing of cultured hepatocytes by allyl alcohol.
Oxidative cell injury in the killing of cultured hepatocytes by allyl alcohol.
复制标题
烯丙醇杀死培养的肝细胞时氧化细胞损伤。
DOI：
10.1016/0003-9861(88)90132-4
复制
发表时间：
1988
影响因子：
3.9
通讯作者：
Farber,JL
中科院分区：
文献类型：
--
作者：
Miccadei,S;Nakae,D;Kyle,ME;Gilfor,D;Farber,JL
烯丙醇对培养肝细胞的杀伤作用取决于醇脱氢酶对反应性亲电试剂丙烯醛的代谢。醇脱氢酶抑制剂吡唑既防止烯丙醇的毒性，又防止谷胱甘肽的迅速耗竭。用铁螯合剂去铁胺或抗氧化剂N，N ' -二苯基-对苯二胺（DPPD）治疗肝细胞，可以阻止细胞被杀死，但不能阻止烯丙醇的代谢和由此产生的谷胱甘肽的消耗。1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）对谷胱甘肽还原酶的抑制使肝细胞对烯丙醇敏感，这一作用与BCNU降低谷胱甘肽的作用无关。烯丙醇杀死细胞之前，细胞脂质发生过氧化，培养物中丙二醛的积累证明了这一点。去铁胺和DPPD在防止细胞被杀死的同时，还能防止脂质过氧化。这些数据表明丙烯醛产生谷胱甘肽的突然消耗，随后是脂质过氧化和细胞死亡。这种氧化细胞损伤被认为是由于无法解毒内源性过氧化氢和随后的铁依赖性强氧化物质的形成。与丙烯醛与细胞大分子的共价结合相比，氧化细胞损伤更能解释丙烯醇的肝毒性。
The killing of cultured hepatocytes by allyl alcohol depended on the metabolism of this hepatotoxin by alcohol dehydrogenase to the reactive electrophile, acrolein. An inhibitor of alcohol dehydrogenase, pyrazole, prevented both the toxicity of allyl alcohol and the rapid depletion of GSH. Treatment of the hepatocytes with a ferric iron chelator, deferoxamine, or an antioxidant,N,N′-diphenyl-p-phenylenediamine (DPPD), prevented the cell killing but not the metabolism of allyl alcohol and the resulting depletion of GSH. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) sensitized the hepatocytes to allyl alcohol, an effect that was not attributable to the reduction in GSH with BCNU. The cell killing with allyl alcohol was preceded by the peroxidation of cellular lipids as evidenced by an accumulation of malondialdehyde in the cultures. Deferoxamine and DPPD prevented the lipid peroxidation in parallel with their protection from the cell killing. These data indicate that acrolein produces an abrupt depletion of GSH that is followed by lipid peroxidation and cell death. Such oxidative cell injury is suggested to result from the inability to detoxify endogenous hydrogen peroxide and the ensuing iron-dependent formation of a potent oxidizing species. Oxidative cell injury more consistently accounts for the hepatotoxicity of allyl alcohol than does the covalent binding of acrolein to cellular macromolecules.