Evaluation of the DNA-damaging and mutagenic activity of oxolinic and pipemidic acids by the granuloma pouch assay

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.