de Flora S, Zanacchi P, Bennicelli C, Camoirano A, Cavanna M, Sciabà L, Cajelli E, Faggin P, Brambilla G
Environ Mutagen. 1982;4(5):605-19. doi: 10.1002/em.2860040512.
Three antihypertensive hydrazine derivatives (hydralazine, dihydralazine, and endralazine) were found to be genotoxic in four in vivo or in vitro short-term test systems. a) In mice, a single ip administration of the LD50 of the three drugs caused a small but statistically significant increase over controls in DNA elution rate, ie, a modest amount of DNA fragmentation, in three of the four organs (liver, lung, kidney, and spleen) tested, DNA damage being absent in lung for hydralazine and endralazine and in liver for dihydralazine. Only for hydralazine DNA lesions were always repaired within 12 hr, in agreement with the constant lack of cumulative effects in mice given five successive daily doses. The rank of potencies was hydralazine greater than dihydralazine greater than endralazine. b) In mice bone marrow cells, all three hydrazine derivatives induced a modest but statistically significant increase over controls in the frequency of sister chromatid exchanges, the rank of potencies being in this case dihydralazine greater than endralazine greater than hydralazine. c) In the Ames reversion test all three drugs behaved as direct-acting mutagens of low potency, whose activity was not influenced by rat liver nor by mouse liver or lung S-9 fractions. Hydralazine and dihydralazine elicited mixed genetic mechanisms of mutations, while endralazine exclusively induced frameshift errors in Salmonella DNA. The recently developed strain TA97 was the most efficient in revealing frameshift errors with all three drugs. d) The selective lethality assays in a battery of two S typhimurium and five E coli strains confirmed the direct genotoxicity of hydralazine, dihydralazine, and endralazine, in order of potency. Potency was evaluated by means of a sensitive and reliable micromethod procedure. Among those investigated, the recA recombination repair and the lexA post-replication repair ("SOS functions") and, to a lesser extent, also the polymerase I mechanism, appeared to contribute to the specific DNA repair with all three drugs, while excision repair systems (uvrA and uvrB) did not appear to be involved.
三种抗高血压肼衍生物（肼屈嗪、双肼屈嗪和恩屈嗪）在四种体内或体外短期测试系统中被发现具有遗传毒性。a）在小鼠中，单次腹腔注射三种药物的半数致死量（LD50）后，在测试的四个器官（肝、肺、肾和脾）中的三个器官中，DNA洗脱率相较于对照组有小幅但具有统计学意义的增加，即出现了适量的DNA片段化，肼屈嗪和恩屈嗪在肺中以及双肼屈嗪在肝中未出现DNA损伤。只有肼屈嗪的DNA损伤总能在12小时内修复，这与连续五天每日给药的小鼠中持续缺乏累积效应一致。效力排序为肼屈嗪＞双肼屈嗪＞恩屈嗪。b）在小鼠骨髓细胞中，所有三种肼衍生物诱导姐妹染色单体交换频率相较于对照组有适度但具有统计学意义的增加，在这种情况下效力排序为双肼屈嗪＞恩屈嗪＞肼屈嗪。c）在艾姆斯回复突变试验中，所有三种药物均表现为低效的直接作用诱变剂，其活性不受大鼠肝以及小鼠肝或肺S - 9组分的影响。肼屈嗪和双肼屈嗪引发混合的基因突变机制，而恩屈嗪仅在沙门氏菌DNA中诱导移码错误。最近开发的TA97菌株在揭示所有三种药物的移码错误方面效率最高。d）在一组两种鼠伤寒沙门氏菌和五种大肠杆菌菌株中的选择性致死率测定证实了肼屈嗪、双肼屈嗪和恩屈嗪的直接遗传毒性，按效力排序。效力通过一种灵敏可靠的微量方法程序进行评估。在所研究的对象中，recA重组修复和lexA复制后修复（“SOS功能”），以及在较小程度上，聚合酶I机制，似乎都对所有三种药物的特异性DNA修复有贡献，而切除修复系统（uvrA和uvrB）似乎未参与其中。
