Maura A, Pino A
Institute of Pharmacology, University of Genoa, Italy.
Mutagenesis. 1988 Sep;3(5):397-401. doi: 10.1093/mutage/3.5.397.
The mutagenic and DNA-damaging activities of oxolinic acid and pipemidic acid were evaluated in the rat granuloma pouch assay. After oral administration at high doses both the chemicals produce DNA alkali-labile sites in granuloma tissue cells, and with oxolinic acid an increase of liver and kidney DNA elution rate was also observed. In contrast, after direct injection into the granuloma tissue, DNA damage was absent. This indicates that DNA lesions are induced by a stable intermediate presumably formed in liver and converted to the ultimate DNA-damaging species in extrahepatic tissues. The simultaneous analysis of 6-thioguanine-resistant cells in the granuloma tissue revealed no statistically significant mutation induction either after local treatment or oral administration. No clear dose-response curve was obtained. However, after oral application in some of the animals an enhanced mutation frequency was detected, and the cloning efficiency of cells exposed to the drugs was reduced even after culturing them for 6 days. The most likely explanation is that functional multilocus mutations are induced which cannot be recovered efficiently at the HGPRT locus.
在大鼠肉芽肿袋试验中评估了恶喹酸和吡哌酸的致突变和DNA损伤活性。高剂量口服给药后，这两种化学物质均在肉芽肿组织细胞中产生DNA碱不稳定位点，并且观察到恶喹酸使肝脏和肾脏DNA洗脱率增加。相反，直接注射到肉芽肿组织后，未出现DNA损伤。这表明DNA损伤是由可能在肝脏中形成并在肝外组织中转化为最终DNA损伤物种的稳定中间体诱导的。对肉芽肿组织中抗6-硫鸟嘌呤细胞的同步分析显示，局部治疗或口服给药后均未诱导出具有统计学意义的突变。未获得明确的剂量反应曲线。然而，在一些动物口服给药后，检测到突变频率增加，并且即使将暴露于药物的细胞培养6天，其克隆效率也降低。最可能的解释是诱导了功能性多位点突变，这些突变在次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HGPRT）位点无法有效恢复。
