Miccadei S, Nakae D, Kyle M E, Gilfor D, Farber J L
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Arch Biochem Biophys. 1988 Sep;265(2):302-10. doi: 10.1016/0003-9861(88)90132-4.
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 evidence 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.
烯丙醇对培养的肝细胞的杀伤作用取决于该肝毒素通过乙醇脱氢酶代谢为活性亲电试剂丙烯醛。乙醇脱氢酶抑制剂吡唑可预防烯丙醇的毒性以及谷胱甘肽（GSH）的快速消耗。用铁螯合剂去铁胺或抗氧化剂N，N'-二苯基对苯二胺（DPPD）处理肝细胞可预防细胞杀伤，但不能阻止烯丙醇的代谢及由此导致的GSH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作用使肝细胞对烯丙醇敏感，这种作用并非归因于BCNU导致的GSH减少。烯丙醇导致细胞杀伤之前，细胞脂质会发生过氧化，培养物中丙二醛的积累证明了这一点。去铁胺和DPPD在防止细胞杀伤的同时也防止了脂质过氧化。这些数据表明，丙烯醛会导致GSH突然耗尽，随后发生脂质过氧化和细胞死亡。这种氧化性细胞损伤被认为是由于无法解毒内源性过氧化氢以及随后铁依赖性形成强氧化性物质所致。与丙烯醛与细胞大分子的共价结合相比，氧化性细胞损伤更能持续解释烯丙醇的肝毒性。
