Dybing E, Holme J A, Gordon W P, Søderlund E J, Dahlin D C, Nelson S D
Mutat Res. 1984 Oct;138(1):21-32. doi: 10.1016/0165-1218(84)90081-8.
Paracetamol and its major ultimate reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) were studied for their genotoxic potential. Neither paracetamol nor NAPQI were found to cause mutations in Salmonella typhimurium, whereas NAPQI was severely cytotoxic to the bacteria. Radiolabelled paracetamol was found to bind covalently to DNA added to mouse-liver microsomal incubations at a rate of 2.6 pmoles/mg DNA/min. Paracetamol also bound covalently to hepatic DNA at a level of 15 pmoles/mg DNA after a hepatotoxic dose of paracetamol to mice. NAPQI caused extensive DNA single-strand breaks as evidenced by alkaline elution of DNA from treated Reuber hepatoma cells. This effect occurred at concentrations which later resulted in cytotoxicity. Paracetamol was shown to induce increased DNA-repair synthesis in isolated mouse-liver cells in monolayer culture, at concentrations where also cytotoxicity was evident. Increased DNA-repair synthesis occurred at lower paracetamol concentrations in cells isolated from mice pretreated with phenobarbital. Taken together, these data show that paracetamol can cause DNA interaction leading to damage at levels which are cytotoxic.
对乙酰氨基酚及其主要最终反应性代谢产物N - 乙酰 - 对苯醌亚胺（NAPQI）的遗传毒性潜力进行了研究。未发现对乙酰氨基酚和NAPQI在鼠伤寒沙门氏菌中引起突变，而NAPQI对该细菌具有严重的细胞毒性。发现放射性标记的对乙酰氨基酚以2.6皮摩尔/毫克DNA/分钟的速率与添加到小鼠肝脏微粒体孵育体系中的DNA共价结合。给小鼠服用肝毒性剂量的对乙酰氨基酚后，对乙酰氨基酚也以15皮摩尔/毫克DNA的水平与肝脏DNA共价结合。碱性洗脱处理过的鲁伯肝癌细胞中的DNA表明，NAPQI会导致广泛的DNA单链断裂。这种效应在随后导致细胞毒性的浓度下出现。在单层培养的分离小鼠肝细胞中，当对乙酰氨基酚的浓度达到明显具有细胞毒性时，对乙酰氨基酚会诱导DNA修复合成增加。在用苯巴比妥预处理过的小鼠分离出的细胞中，对乙酰氨基酚在较低浓度时就会出现DNA修复合成增加。综上所述，这些数据表明，对乙酰氨基酚可导致DNA相互作用，在具有细胞毒性的水平上造成损伤。
