Kyle M E, Nakae D, Serroni A, Farber J L
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Mol Pharmacol. 1988 Oct;34(4):584-9.
The toxicity of acetaminophen was studied in hepatocytes cultured from phenobarbital-induced male rats. Such cells were less sensitive to acetaminophen than similar ones cultured from animals induced with 3-methylcholanthrene. In both cases, the toxicity of acetaminophen depended on its metabolism. Inhibition of glutathione reductase with 1,3-(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the toxicity of acetaminophen in the presence or absence of 100 mM acetone, an agent that activates the mixed function oxidation of the toxin. BCNU enhanced the rate and extent of the depletion of GSH in the presence or absence of acetone. Pretreatment of the hepatocytes with the ferric iron chelator deferoxamine or addition to the culture medium of the antioxidant N,N'-diphenyl-p-phenylenediamine prevented the toxicity of acetaminophen in the presence of BCNU whether or not there was acetone in the cultures. BCNU similarly potentiated the hepatotoxicity of acetaminophen in the intact, phenobarbital-induced rat. These data indicate that the mechanism of the killing of hepatocytes induced with phenobarbital is similar to that reported previously with hepatocytes prepared from animals induced with 3-methylcholanthrene. In both cases it would seem that the liver cells are killed by acetaminophen as a result of an oxidative stress that accompanies the metabolism of this hepatotoxin.
对苯巴比妥诱导的雄性大鼠培养的肝细胞进行了对乙酰氨基酚毒性的研究。与从3-甲基胆蒽诱导的动物培养的类似细胞相比，此类细胞对乙酰氨基酚的敏感性较低。在这两种情况下，对乙酰氨基酚的毒性都取决于其代谢。用1,3-(2-氯乙基)-1-亚硝基脲（卡莫司汀，BCNU）抑制谷胱甘肽还原酶，无论是否存在100 mM丙酮（一种激活毒素混合功能氧化的试剂），均会增强对乙酰氨基酚的毒性。无论是否存在丙酮，BCNU都会提高谷胱甘肽（GSH）消耗的速率和程度。用铁螯合剂去铁胺预处理肝细胞或在培养基中添加抗氧化剂N,N'-二苯基对苯二胺，无论培养物中是否存在丙酮，均可防止在BCNU存在的情况下对乙酰氨基酚的毒性。BCNU同样增强了完整的、苯巴比妥诱导的大鼠中对乙酰氨基酚的肝毒性。这些数据表明，苯巴比妥诱导的肝细胞杀伤机制与先前报道的从3-甲基胆蒽诱导的动物制备的肝细胞的杀伤机制相似。在这两种情况下，似乎肝细胞都是由于这种肝毒素代谢伴随的氧化应激而被对乙酰氨基酚杀死的。
