Farber J L, Leonard T B, Kyle M E, Nakae D, Serroni A, Rogers S A
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Arch Biochem Biophys. 1988 Dec;267(2):640-50. doi: 10.1016/0003-9861(88)90072-0.
Acetaminophen killed cultured hepatocytes prepared from male rats induced with 3-methylcholanthrene by two distinct mechanisms. With 0.5 to 5 mM acetaminophen, cell killing within 4 h depended on the inhibition of glutathione reductase by 1,3-bis(chloroethyl)-1-nitrosourea (BCNU) and was accompanied by the peroxidation of cellular lipids as assessed by the accumulation of malondialdehyde. The antioxidant diphenylphenylenediamine (DPPD) prevented both the peroxidation of lipids and the death of the cells. By contrast, DPPD had no effect on the metabolism of acetaminophen as assessed by the extent of the covalent binding of [3H]acetaminophen; by the rate and extent of the depletion of glutathione; and by the accumulation of acetaminophen metabolites in the culture medium. It is concluded that the peroxidation of the phospholipids of cellular membranes is the mechanism whereby 0.5 to 5 mM acetaminophen lethally injures cultured hepatocytes. With 10-20 mM acetaminophen, cell killing at 4 h still depended on BCNU. However, the amount of malondialdehyde in the cultures progressively decreased in parallel with the decreasing ability of DPPD to protect the cells. With 20 mM acetaminophen, there was no evidence of lipid peroxidation, and DPPD had no protective effect. Thus, a second mechanism of lethal cell injury with 10-20 mM acetaminophen is independent of lipid peroxidation and insensitive to antioxidants.
对乙酰氨基酚通过两种不同机制杀死了由3-甲基胆蒽诱导的雄性大鼠制备的培养肝细胞。在0.5至5 mM对乙酰氨基酚作用下，4小时内细胞死亡取决于1,3-双（氯乙基）-1-亚硝基脲（BCNU）对谷胱甘肽还原酶的抑制作用，并伴有细胞脂质过氧化，这可通过丙二醛的积累来评估。抗氧化剂二苯基苯二胺（DPPD）可防止脂质过氧化和细胞死亡。相比之下，通过[3H]对乙酰氨基酚的共价结合程度、谷胱甘肽消耗的速率和程度以及培养基中对乙酰氨基酚代谢物的积累来评估，DPPD对对乙酰氨基酚的代谢没有影响。得出的结论是，细胞膜磷脂的过氧化是0.5至5 mM对乙酰氨基酚致死性损伤培养肝细胞的机制。在10 - 20 mM对乙酰氨基酚作用下，4小时时细胞死亡仍取决于BCNU。然而，培养物中丙二醛的量随着DPPD保护细胞能力的下降而逐渐减少。在20 mM对乙酰氨基酚作用下，没有脂质过氧化的证据，DPPD也没有保护作用。因此，10 - 20 mM对乙酰氨基酚致死性细胞损伤的第二种机制与脂质过氧化无关，且对抗氧化剂不敏感。
