Clement B, Schmezer P, Weber H, Schlehofer J R, Schmitt S, Pool B L
Institute for Pharmaceutical Chemistry, Philipps University, Marburg, Federal Republic of Germany.
J Cancer Res Clin Oncol. 1988;114(4):363-8. doi: 10.1007/BF02128179.
The genotoxic potentials of benzamidine and benzamidoxime were determined to study the toxicological relevance of the metabolic N-oxygenation (N-hydroxylation) of benzamidines to benzamidoximes. Benzamidoxime induced DNA single-strand breaks (in rat hepatocytes) and DNA amplification in SV40-transformed hamster cells. In the experiments performed, benzamidine itself was only marginally positive in the hepatocyte/DNA single-strand break assay. Since these cells possess an intact metabolization apparatus, the biological activities may be attributed to toxic and genotoxic metabolites formed by biotransformation. In the Salmonella typhimurium mutagenicity test (TA 98 and TA 100) benzamidoxime alone exhibited a low mutagenicity in the TA 98 strain in the presence of rabbit liver S-9 fractions. These results permit recognition of the metabolic N-hydroxylation of benzamidines to benzamidoximes as a process to toxication. Indirect evidence for the formation of a glucuronide of benzamidoxime has been obtained from in vitro experiments, but it could not be established that this process was a decisive factor in the genotoxicity of benzamidoxime.
测定了苯甲脒和苯甲脒肟的遗传毒性潜力，以研究苯甲脒代谢性N-氧化（N-羟基化）生成苯甲脒肟的毒理学相关性。苯甲脒肟可诱导DNA单链断裂（在大鼠肝细胞中）以及SV40转化的仓鼠细胞中的DNA扩增。在进行的实验中，苯甲脒本身在肝细胞/DNA单链断裂试验中仅呈弱阳性。由于这些细胞具有完整的代谢装置，其生物活性可能归因于生物转化形成的有毒和遗传毒性代谢产物。在鼠伤寒沙门氏菌致突变性试验（TA 98和TA 100）中，单独的苯甲脒肟在兔肝S-9组分存在的情况下，在TA 98菌株中表现出低致突变性。这些结果表明苯甲脒代谢性N-羟基化生成苯甲脒肟是一个中毒过程。体外实验已获得苯甲脒肟葡糖醛酸苷形成的间接证据，但无法确定该过程是否是苯甲脒肟遗传毒性的决定性因素。
