Presta M, Legati F, Chiesa R, Dell'Era P, Ragnotti G
Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Italy.
Carcinogenesis. 1990 Feb;11(2):261-5. doi: 10.1093/carcin/11.2.261.
A single administration of the sex-dependent hepatocarcinogenic beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)3-tert-butylamino-propan-2-ol (DL-ZAMI 1305) induces liver DNA damage, as evaluated by alkaline sucrose gradient analysis, in female but not in male Fisher 344 rats. The shift of the methyl-group from the 3-position of the aromatic ring of DL-ZAMI 1305 to the 4- and 5-position causes the progressive decrease of the genotoxic activity of the molecule. No effect on the DNA-damaging capacity of DL-ZAMI 1305 is instead observed when the NO2 group of the aromatic ring is reduced to an NH2 group. Bis-demethylation of the side chain of DL-ZAMI 1305, or its modification to an alpha-hydroxicarboxylic acid or glycol, increases the DNA-damaging capacity of the molecule, which becomes genotoxic also for the liver of the male rat. Thus, modifications of the chemical structure of the aromatic ring or of the side chain of DL-ZAMI 1305 affect the genotoxic activity of the molecule both in male and female rat liver. The modifications of the side chain of DL-ZAMI 1305 investigated in the present work are likely to occur in vivo as a consequence of the hepatic metabolism of the molecule. Sex-dependent differences in the activity of the liver drug-metabolizing system might explain the different genotoxic and oncogenic activity of DL-ZAMI 1305 in the two sexes.
单次给予具有性别依赖性的致癌β受体阻滞剂DL-1-(2-硝基-3-甲基苯氧基)-3-叔丁氨基-2-丙醇（DL-ZAMI 1305）后，通过碱性蔗糖梯度分析评估发现，雌性Fisher 344大鼠肝脏出现DNA损伤，而雄性大鼠未出现。DL-ZAMI 1305芳香环3位上的甲基转移至4位和5位会导致该分子遗传毒性活性逐渐降低。相反，当芳香环的NO2基团还原为NH2基团时，未观察到对DL-ZAMI 1305的DNA损伤能力有影响。DL-ZAMI 1305侧链的双去甲基化，或将其修饰为α-羟基羧酸或二醇，会增加该分子的DNA损伤能力，其对雄性大鼠肝脏也具有遗传毒性。因此，DL-ZAMI 1305芳香环或侧链化学结构的改变会影响该分子在雄性和雌性大鼠肝脏中的遗传毒性活性。本研究中所探究的DL-ZAMI 1305侧链修饰可能是该分子肝脏代谢的结果而在体内发生。肝脏药物代谢系统活性的性别依赖性差异可能解释了DL-ZAMI 1305在两性中不同的遗传毒性和致癌活性。
