University of Kansas Medical Center, Department of Pharmacology, Toxicology & Therapeutics, Kansas City, KS, USA.
Murray & Associates, San Jose, CA, USA.
Regul Toxicol Pharmacol. 2021 Mar;120:104859. doi: 10.1016/j.yrtph.2020.104859. Epub 2021 Jan 1.
In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.
2019 年，加利福尼亚州环境健康危害评估办公室（OEHHA）启动了对扑热息痛致癌危害潜力的审查。在此审查的同时，我们评估了与以下相关的机制数据：细胞事件的步骤和时间，包括治疗推荐剂量（≤4 克/天）和更高剂量的扑热息痛可能导致肝毒性，以评估这些变化是否表明扑热息痛是致癌危害。在治疗推荐剂量下，扑热息痛形成有限量的 N-乙酰对苯醌亚胺（NAPQI）而没有不良细胞效应。在扑热息痛过量后，可能会有更多的 NAPQI 形成和谷胱甘肽耗竭，这可能导致线粒体功能障碍和 DNA 损伤，但仅在导致细胞死亡的剂量下 - 因此，扑热息痛不太可能引起核内稳定的遗传损伤，这表明对人类具有遗传毒性或致癌危害。综合数据表明，与致癌性相关的机制缺乏合理性，与啮齿动物癌症生物测定、本期刊登的相关文献中的流行病学结果以及多个国际卫生当局的结论一致。
