Rannug U, Holme J A, Hongslo J K, Srám R
Department of Genetic and Cellular Toxicology, Stockholm University, Sweden.
Mutat Res. 1995 Mar;327(1-2):179-200. doi: 10.1016/0027-5107(94)00184-7.
During the last years, several reports have indicated genotoxic effects of paracetamol, a widely used non-prescription analgesic and antipyretic drug. Thus, a careful evaluation of a possible genotoxic effect related to paracetamol use is warranted. Studies in vitro and in vivo indicate that the reactive metabolite of paracetamol can bind irreversibly to DNA and cause DNA strand breaks. Paracetamol inhibits both replicative DNA synthesis and DNA repair synthesis in vitro and in experimental animals. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. On the other hand, a co-mutagenic effect of paracetamol has been reported. Furthermore, paracetamol increases the frequency of chromosomal damage in mammalian cell lines, isolated human lymphocytes and experimental animals. Two independent studies have shown an increase in chromosomal damage in lymphocytes of human volunteers after intake of therapeutic doses of paracetamol, whereas a third study was negative. Paracetamol-induced chromosomal damage appears to be caused by an inhibition of ribonucleotide reductase. This indicates that a threshold level for the paracetamol-induced chromosomal damage may exist. Genotoxic effects of paracetamol have, however, been demonstrated both in vitro and in vivo at or near therapeutic concentrations. The data indicate that the use of paracetamol may contribute to an increase in the total burden of genotoxic damage in man. Thus, there may be a need to evaluate the therapeutic benefit of paracetamol, taking into consideration not only its potential to induce acute and chronic organ damage, but also genotoxic effects.
在过去几年中，几份报告指出了对乙酰氨基酚（一种广泛使用的非处方止痛和解热药物）的遗传毒性作用。因此，有必要仔细评估与使用对乙酰氨基酚相关的可能的遗传毒性作用。体外和体内研究表明，对乙酰氨基酚的活性代谢物可与DNA不可逆结合并导致DNA链断裂。对乙酰氨基酚在体外和实验动物中均抑制复制性DNA合成和DNA修复合成。对乙酰氨基酚在细菌或哺乳动物细胞中均不会引起基因突变。另一方面，有报道称对乙酰氨基酚具有共诱变作用。此外，对乙酰氨基酚会增加哺乳动物细胞系、分离的人淋巴细胞和实验动物中的染色体损伤频率。两项独立研究表明，人类志愿者摄入治疗剂量的对乙酰氨基酚后，淋巴细胞中的染色体损伤增加，而第三项研究结果为阴性。对乙酰氨基酚诱导的染色体损伤似乎是由核糖核苷酸还原酶的抑制引起的。这表明可能存在对乙酰氨基酚诱导的染色体损伤的阈值水平。然而，在治疗浓度或接近治疗浓度时，对乙酰氨基酚的遗传毒性作用已在体外和体内得到证实。数据表明，使用对乙酰氨基酚可能会导致人类遗传毒性损伤总负担的增加。因此，可能有必要评估对乙酰氨基酚的治疗益处，不仅要考虑其诱导急性和慢性器官损伤的潜力，还要考虑其遗传毒性作用。
