Species Variation in the Genotoxicity of Batracylin

Abstract

Batracylin (8-aminoisoindolo[1,2-b]quinazolin-1 2(10H)-one), an experimental chemotherapeutic agent, is a heterocyclic aryl amine. The presence of the free amino group suggests that this compound may be a carcinogen. Since many carcinogens or their product interact with DNA, the genotoxicity of batracylin was evaluated. The mutagenicity of batracylin was tested in Salmonella typhimurium (TA 98, TA 100, TA 102) with and without Aroclor-induced rat liver S9. Batracylin induced histidine revertants in all three strains with a higher number of mutants formed in the presence of S9. The maximum mutant incidence as well as the lowest concentration inducing a positive response was observed with TA 98 which detects frameshift mutations. Genotoxicity was further assessed by the induction of DNA repair in hepatocytes isolated from F-344 rats and two mouse strains differing in N-acetyltransferase activity. In hepatocytes from male F-344 rats, batracylin elicited DNA repair at concentrations of 5 × 10 −8 to 10 −6 M. Maximum repair was observed in both strains of mice at 5 × 10 −5 M batracylin, a concentration that was toxic to rat hepatocytes. Cells isolated from the rapid acetylator strain, C57BL/6J, tended to have higher net grain counts than observed with the slow acetylator (A/J) strain, although the differences were not statistically significant. These results demonstrate that batracylin is genotoxic in bacteria and mammalian cells. The species variation in the genotoxicity of batracylin is consistent with in vivo toxicity studies.