Robbiano L, Carlo P, Finollo R, Brambilla G
Institute of Pharmacology, University of Genoa, Italy.
Toxicol Appl Pharmacol. 1990 Jan;102(1):186-90. doi: 10.1016/0041-008x(90)90095-c.
Chlordiazepoxide (CDE) reacts in acidic conditions with NaNO2 yielding N-nitrosochlordiazepoxide (NO-CDE), previously shown to exert genotoxic effects in some in vitro systems. The possible intragastric nitrosation of CDE to NO-CDE has been investigated in rats given by gavage high single doses of this benzodiazepine along with NaNO2. Liver DNA fragmentation, as revealed by both DNA alkaline elution and a more sensitive viscometric method, was found to occur consistently and to be essentially independent of the molar ratio drug/nitrite or of gastric pH. The significant increase in the frequency of DNA lesions observed in rats treated for 15 successive days indicates that DNA repair did not keep pace with the accumulation of the damage. Oral administration of single doses of NO-CDE induced similar dose-dependent amounts of DNA fragmentation in liver, gastric mucosa, and brain. Due to the demonstrated absence of carcinogenic activity in rodents, the present results should be interpreted solely as indicating that NO-CDE is intrinsically capable of producing DNA lesions in vivo, an effect by itself not sufficient to induce tumor growth.
氯氮䓬（CDE）在酸性条件下与亚硝酸钠反应生成N-亚硝基氯氮䓬（NO-CDE），此前已证明其在某些体外系统中具有遗传毒性作用。通过灌胃给予大鼠高单次剂量的这种苯二氮䓬类药物以及亚硝酸钠，研究了CDE在胃内可能亚硝化生成NO-CDE的情况。通过DNA碱性洗脱和一种更灵敏的粘度测定法发现，肝脏DNA片段化持续发生，且基本上与药物/亚硝酸盐的摩尔比或胃内pH值无关。连续15天接受治疗的大鼠中观察到的DNA损伤频率显著增加，表明DNA修复未能跟上损伤的积累。口服单剂量的NO-CDE在肝脏、胃黏膜和大脑中诱导出类似剂量依赖性的DNA片段化。由于已证明在啮齿动物中不存在致癌活性，目前的结果仅应解释为表明NO-CDE在体内具有产生DNA损伤的内在能力，但其本身不足以诱导肿瘤生长。
