Martelli A, Allavena A, Sottofattori E, Brambilla G
Institute of Pharmacology, University of Genoa, Italy.
Toxicol Lett. 1994 Sep;73(3):185-91. doi: 10.1016/0378-4274(94)90057-4.
The N-nitroso derivatives formed by the in vitro reaction of 5 beta-adrenergic-blocking drugs with sodium nitrite and previously found to induce DNA fragmentation and repair in primary cultures of both rat and human hepatocytes were tested for their ability to exert a clastogenic effect in vivo. In partially hepatectomized rats given by gavage a single dose of 1000 mg/kg, all 5 N-nitroso derivatives caused a statistically significant increase in the frequency of micronucleated hepatocytes, the clastogenic potencies of NO-propranolol, NO-metoprolol, and NO-nadolol being slightly greater than those of NO-atenolol and NO-sotalol. In contrast, none of them produced a significant increase in the frequency of micronucleated polychromatic erythrocytes in the bone marrow and the spleen. For all 5 N-nitroso derivatives the in vivo clastogenic potency, i.e. the ratio between the number of micronuclei observed in the liver and the dose administered, was markedly lower than the in vitro DNA-damaging potency calculated as the ratio between the amount of DNA fragmentation and the concentration tested. This suggests a preferential detoxification in vivo of the 5 N-nitroso derivatives.
5种β-肾上腺素能阻滞剂与亚硝酸钠在体外反应形成的N-亚硝基衍生物，先前已发现其可诱导大鼠和人原代肝细胞DNA片段化和修复，现对其在体内产生致染色体断裂效应的能力进行了测试。在接受1000 mg/kg单剂量灌胃的部分肝切除大鼠中，所有5种N-亚硝基衍生物均导致微核化肝细胞频率出现统计学上的显著增加，其中NO-普萘洛尔、NO-美托洛尔和NO-纳多洛尔的致染色体断裂效力略高于NO-阿替洛尔和NO-索他洛尔。相比之下，它们均未使骨髓和脾脏中微核多染红细胞的频率显著增加。对于所有5种N-亚硝基衍生物，体内致染色体断裂效力（即肝脏中观察到的微核数量与给药剂量之比）明显低于体外DNA损伤效力（计算为DNA片段化量与测试浓度之比）。这表明5种N-亚硝基衍生物在体内存在优先解毒作用。
