Bergman K, Müller L, Teigen S W
Medical Products Agency, Uppsala, Sweden.
Mutat Res. 1996 Feb 1;349(2):263-88. doi: 10.1016/0027-5107(95)00185-9.
The publication of several studies reporting genotoxic effects of paracetamol, one of the world's most popular over-the-counter drugs, has raised the question of regulatory action. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. There are, however, published data giving clear evidence that paracetamol causes chromosomal damage in vitro in mammalian cells at high concentrations and indicating that similar effects occur in vivo at high dosages. Available data point to three possible mechanisms of paracetamol-induced genotoxicity: (1) inhibition of ribonucleotide reductase; (2) increase in cytosolic and intranuclear Ca2+ levels; (3) DNA damage caused by NAPQI after glutathione depletion. All mechanisms involve dose thresholds. Studies of the relationship between genotoxicity and toxic effects in the rat (induction of micronuclei in rat bone marrow including dose-response relationship, biotransformation of paracetamol at different dosages, concomitant toxicity and biochemical markers) have recently been completed. These studies, which employed doses ranging from the dose resulting in human therapeutic peak plasma levels to highly toxic doses, give convincing evidence that genotoxic effects of paracetamol appear only at dosages inducing pronounced liver and bone marrow toxicity and that the threshold level for genotoxicity is not reached at therapeutic dosage. Reliable studies on the ability of paracetamol to affect germ cell DNA are not available. However, based on the amount of drug likely to reach germ cells and the evidence of thresholds, paracetamol is not expected to cause heritable damage in man. Various old and poorly designed long-term studies of paracetamol in the mouse and rat have given equivocal results. A few of these studies showed increased incidence of liver and bladder tumours at hepatotoxic doses. National Toxicology Program (U.S.A.) feeding studies have shown that paracetamol is non-carcinogenic when given at non-hepatotoxic doses up to 300 mg/kg/d to the rat and up to 1000 mg/kg/d to the mouse. Taking into account the knowledge of the hepatotoxicity and metabolism of paracetamol and the existence of thresholds for its genotoxicity, the animal studies do not indicate a carcinogenic potential at non-hepatotoxic dose levels. Based on this updated assessment of the genotoxicity and carcinogenicity of paracetamol, it is concluded that there is no need for regulatory action.
几项研究报告了全球最常用的非处方药之一对乙酰氨基酚的遗传毒性作用，这引发了监管行动的问题。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。然而，已发表的数据明确表明，对乙酰氨基酚在高浓度下会在体外导致哺乳动物细胞染色体损伤，并且表明在高剂量下体内也会出现类似效应。现有数据指出了对乙酰氨基酚诱导遗传毒性的三种可能机制：（1）抑制核糖核苷酸还原酶；（2）细胞溶质和细胞核内钙离子水平升高；（3）谷胱甘肽耗竭后由N - 乙酰 - 对苯醌亚胺（NAPQI）引起的DNA损伤。所有机制都涉及剂量阈值。最近完成了关于大鼠遗传毒性与毒性效应之间关系的研究（包括大鼠骨髓中微核的诱导，剂量 - 反应关系，不同剂量下对乙酰氨基酚的生物转化，伴随毒性和生化标志物）。这些研究采用了从导致人体治疗性血浆峰值水平的剂量到高毒性剂量的范围，提供了令人信服的证据，即对乙酰氨基酚的遗传毒性效应仅在诱导明显肝脏和骨髓毒性的剂量下出现，并且在治疗剂量下未达到遗传毒性的阈值水平。关于对乙酰氨基酚影响生殖细胞DNA能力的可靠研究尚不可得。然而，基于可能到达生殖细胞的药物量以及阈值证据，预计对乙酰氨基酚不会对人类造成可遗传的损害。对乙酰氨基酚在小鼠和大鼠中进行的各种陈旧且设计不佳的长期研究结果不一。其中一些研究表明，在肝毒性剂量下肝脏和膀胱肿瘤的发生率增加。美国国家毒理学计划的喂养研究表明，以高达300毫克/千克/天的非肝毒性剂量给予大鼠以及高达1000毫克/千克/天的剂量给予小鼠时，对乙酰氨基酚无致癌性。考虑到对乙酰氨基酚的肝毒性和代谢知识以及其遗传毒性阈值的存在，动物研究并未表明在非肝毒性剂量水平下有致癌潜力。基于对乙酰氨基酚遗传毒性和致癌性的这一最新评估，得出结论认为无需采取监管行动。
