Thorgeirsson S S, Wirth P J
J Toxicol Environ Health. 1977 Mar;2(4):873-81. doi: 10.1080/15287397709529485.
In vivo and in vitro covalent binding of foreign chemicals to tissue macromolecules via metabolic activation is described, using the analgesic acetaminophen as an example. Acetaminophen is metabolized through a variety of pathways. The arylating metabolite is formed by a cytochrome P-450 dependent N-hydroxylation process. The resulting hydroxamic acid is then conjugated with glutathione, and the resulting conjugate is subsequently excreted as the mercapturic acid in the urine. It is not until the glutathione concentration is reduced to about 20% of the initial concentration that covalent binding of acetaminophen to amino acids of proteins occurs and subsequent liver necrosis is seen. The extent of in vitro binding correlates with treatments that alter hepatic necrosis and in vivo binding, indicating that in vitro binding is a valid index of acetaminophen hepatotoxicity. A simple bacterial test system for detecting chemical carcinogens as mutagens is described.
以镇痛药对乙酰氨基酚为例，描述了外源化学物质通过代谢活化与组织大分子的体内和体外共价结合。对乙酰氨基酚通过多种途径代谢。芳基化代谢物是通过细胞色素P-450依赖性N-羟基化过程形成的。生成的异羟肟酸随后与谷胱甘肽结合，生成的结合物随后以巯基尿酸的形式随尿液排出。直到谷胱甘肽浓度降低到初始浓度的约20%时，对乙酰氨基酚才会与蛋白质的氨基酸发生共价结合，并随后出现肝坏死。体外结合程度与改变肝坏死的处理和体内结合相关，表明体外结合是对乙酰氨基酚肝毒性的有效指标。描述了一种用于检测化学致癌物作为诱变剂的简单细菌测试系统。
