Albano E, Poli G, Chiarpotto E, Biasi F, Dianzani M U
Chem Biol Interact. 1983 Dec;47(3):249-63. doi: 10.1016/0009-2797(83)90161-8.
Treatment of isolated hepatocytes from 3-methylcholanthrene induced rats with 1 mM paracetamol has been found to greatly decrease cellular reduced glutathione (GSH) content and to promote lipid peroxidation, evaluated as malonaldehyde (MDA) production and conjugated diene absorbance. A similar dosing of hepatocytes from phenobarbital-induced or normal rats is ineffective in that respect. On the other hand, the aspecific stimulation of the cytochrome P-450-mediated paracetamol activation due to acetone addition further increases GSH depletion as well as MDA production. Isolated hepatocytes with basal low GSH content are also more susceptible to paracetamol-induced lipid peroxidation, indicating that the rate of the drug metabolism and the cellular GSH content are critical factors in the determination of such peroxidative attack. In isolated mouse liver cells paracetamol does not require preliminary cytochrome P-450 induction to stimulate MDA formation, even at concentrations ineffective in rat cells. However, 5 mM paracetamol, despite a great depletion of cellular GSH content, does not promote MDA formation either in the rat or in the mouse hepatocytes. This effect may be due to the ability of paracetamol to scavenge lipid peroxides under defined conditions, as tested in various lipid peroxidizing systems. Membrane leakage of lactate dehydrogenase (LDH) is evident in paracetamol treated cells undergoing lipid peroxidation, but not when MDA formation is inhibited by high doses of the drug or by addition of anti-oxidants such as alpha-tocopherol and diphenylphenylenediamine (DPPD). Nevertheless in these conditions the covalent binding of activated paracetamol metabolites is not affected, suggesting that lipid peroxidation might play a role in the pathogenesis of liver damage following paracetamol overdose.
已发现，用1 mM对乙酰氨基酚处理经3 - 甲基胆蒽诱导的大鼠的分离肝细胞，会显著降低细胞内还原型谷胱甘肽（GSH）含量，并促进脂质过氧化，脂质过氧化以丙二醛（MDA）生成量和共轭二烯吸光度来评估。在这方面，用类似剂量处理苯巴比妥诱导的大鼠或正常大鼠的肝细胞则无效。另一方面，由于添加丙酮导致细胞色素P - 450介导的对乙酰氨基酚活化的非特异性刺激，会进一步增加GSH消耗以及MDA生成。基础GSH含量低的分离肝细胞对对乙酰氨基酚诱导的脂质过氧化也更敏感，这表明药物代谢速率和细胞内GSH含量是决定此类过氧化攻击的关键因素。在分离的小鼠肝细胞中，对乙酰氨基酚即使在对大鼠细胞无效的浓度下，也不需要预先诱导细胞色素P - 450就能刺激MDA形成。然而，5 mM对乙酰氨基酚尽管会使细胞内GSH含量大幅减少，但在大鼠或小鼠肝细胞中均不会促进MDA形成。这种效应可能是由于对乙酰氨基酚在特定条件下清除脂质过氧化物的能力，这已在各种脂质过氧化系统中得到测试。在经历脂质过氧化的对乙酰氨基酚处理的细胞中，乳酸脱氢酶（LDH）的膜泄漏很明显，但当高剂量药物或添加抗氧化剂如α - 生育酚和二苯基苯二胺（DPPD）抑制MDA形成时则不会出现这种情况。然而，在这些条件下，活化的对乙酰氨基酚代谢物的共价结合不受影响，这表明脂质过氧化可能在对乙酰氨基酚过量后肝损伤的发病机制中起作用。
