期刊
REGULATORY TOXICOLOGY AND PHARMACOLOGY
卷 118, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2020.104788
关键词
Acetaminophen; Paracetamol; Safety; Carcinogenicity; Hazard; Simulations; Modeling; Mechanisms; Toxicity
资金
- Consumer Healthcare Products Association
- Johnson & Johnson Consumer, Inc
In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g. baseline glutathione (GSH) levels, pharmacokinetics, and capacity of hepatic antioxidants) leads to potential differences in carcinogenic hazard potential at different dosing schemes: maximum labeled doses of 4 g/day, repeated doses above the maximum labeled dose (>4-12 g/day), and acute overdoses of acetaminophen (>15 g). This was achieved by performing simulations of acetaminophen exposure in thousands of diverse virtual patients scenarios using the DILIsym (R) Quantitative Systems Toxicology (QST) model. Simulations included assessments of the dose and exposure response for toxicity and mode of cell death based on evaluations of the kinetics of changes of: GSH, N-acetyl-pbenzoquinone-imine (NAPQI), protein adducts, mitochondrial dysfunction, and hepatic cell death. Results support that, at therapeutic doses, cellular GSH binds to NAPQI providing sufficient buffering capacity to limit protein adduct formation and subsequent oxidative stress. Simulations evaluating repeated high-level supra therapeutic exposures or acute overdoses indicate that cell death precedes DNA damage that could result in carcinogenicity and thus acetaminophen does not present a carcinogenicity hazard to humans at any dose.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据