Carlo P, Finollo R, Ledda A, Brambilla G
Institute of Pharmacology, University of Genoa, Italy.
Fundam Appl Toxicol. 1989 Jan;12(1):34-41. doi: 10.1016/0272-0590(89)90059-6.
Literature data on mutagenic-carcinogenic activity of benzodiazepines are scarce, restricted to few of them, and contradictory. Consequently, in order to provide additional information for the assessment of the genotoxic risk connected with the use of this family of drugs, 32 benzodiazepines of various chemical structure have been tested for their capability to induce DNA damage in vivo, which is considered a sensitive index of potential mutagenic-carcinogenic activity. The frequency of DNA single-strand breaks and/or alkali-labile sites was checked in the liver of rats given orally a single dose (1 mmol/kg) or 15 successive daily doses (0.2 mmol/kg) by the use of a new viscometric technique capable of detecting one DNA lesion per 10(10) Da. Statistically significant changes of viscometric parameters indicative of liver DNA fragmentation were absent with all 32 benzodiazepines, after both acute and subacute treatments. Since the doses tested in rats were from 100 to more than 5000 times higher than doses usually administered to humans, these negative results are in favor of the absence of mutagenic-carcinogenic effects in patients taking benzodiazepines.
关于苯二氮䓬类药物诱变致癌活性的文献数据稀缺，仅限于少数几种药物，且相互矛盾。因此，为了提供更多信息以评估与使用这类药物相关的遗传毒性风险，对32种化学结构各异的苯二氮䓬类药物进行了体内诱导DNA损伤能力的测试，DNA损伤被认为是潜在诱变致癌活性的敏感指标。通过使用一种新的粘度测定技术，能够检测每10(10)Da一个DNA损伤，在口服单剂量(1 mmol/kg)或连续15天每日剂量(0.2 mmol/kg)的大鼠肝脏中检查DNA单链断裂和/或碱不稳定位点的频率。在急性和亚急性治疗后，所有32种苯二氮䓬类药物均未出现表明肝脏DNA片段化的粘度测定参数的统计学显著变化。由于在大鼠中测试的剂量比通常给人类施用的剂量高100至5000倍以上，这些阴性结果表明服用苯二氮䓬类药物的患者不存在诱变致癌作用。
