Griffin R J, Dudley C N, Cunningham M L
Chemistry Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Fundam Appl Toxicol. 1996 Jan;29(1):147-54. doi: 10.1006/faat.1996.0016.
The National Toxicology Program (NTP) recently determined that the commonly prescribed sedative hypnotic agent oxazepam is a mouse liver carcinogen. Many other benzodiazepines are metabolized to oxazepam resulting in further human exposure to this drug. This has resulted in considerable interest in the mechanism of oxazepam-mediated mouse liver carcinogenesis for use in human risk assessment. Several directions for mechanistic research were examined in this study. B6C3F1 mice were treated with oxazepam-dosed feed at 125 (noncarcinogenic) and 2500 ppm (carcinogenic) for 3, 7, 10, and 21 days. Cell proliferation in liver, cytochrome P450 induction, free radical formation, GSH depletion, and levels of circulating thyroid-stimulating hormone (TSH) were analyzed at these time points. Increased levels of hepatic cell proliferation were observed by 7 days at 125 ppm and by 10 days at 2500 ppm. Microsomal enzyme induction also occurred and was associated with elevated plasma TSH levels. Hepatic GSH levels were slightly depressed but there was no evidence of increased oxidative stress. A similar pattern of biochemical events has been observed to occur during dosed feed treatment with phenobarbital. These results suggest that oxazepam and phenobarbital may induce carcinogenesis by similar mechanisms in mice.
美国国家毒理学计划（NTP）最近确定，常用的镇静催眠药奥沙西泮是一种小鼠肝脏致癌物。许多其他苯二氮䓬类药物会代谢为奥沙西泮，导致人类进一步接触这种药物。这引发了人们对奥沙西泮介导的小鼠肝脏致癌作用机制的极大兴趣，以便用于人类风险评估。本研究考察了几个机制研究方向。用含125 ppm（非致癌剂量）和2500 ppm（致癌剂量）奥沙西泮的饲料对B6C3F1小鼠进行处理，为期3、7、10和21天。在这些时间点分析肝脏中的细胞增殖、细胞色素P450诱导、自由基形成、谷胱甘肽（GSH）消耗以及循环甲状腺刺激激素（TSH）水平。在125 ppm剂量下，7天时观察到肝细胞增殖水平升高；在2500 ppm剂量下，10天时观察到肝细胞增殖水平升高。微粒体酶诱导也发生了，并且与血浆TSH水平升高有关。肝脏GSH水平略有下降，但没有氧化应激增加的证据。在用苯巴比妥进行饲料给药处理期间也观察到了类似的生化事件模式。这些结果表明，奥沙西泮和苯巴比妥可能通过类似机制在小鼠中诱导致癌作用。
