ANALYSIS OF METABOLISM AND GENOTOXICITY OF 5-NITRO-3-THIOPHENECARBOXANILIDES IN BACTERIAL, MAMMALIAN AND HUMAN-CELLS

5-nitro-3-thiophenecarboxanilide (NTCA3) was clearly mutagenic in Salm onella typhimurium strains TA98, YG1021 (the strain with elevated nitr oreductase) and YG1024 (the strain with elevated O-acetyltransferase) and only slightly mutagenic at the gpt locus in AS52 cells. Clastogeni c activity in human lymphocytes was dependent on the length of exposur e: detectable chromosome aberrations were observed following a 24 h tr eatment period, but not after 3 h exposure, S9 increased genotoxicity in both mammalian cells and human lymphocytes. Metabolites formed by i ncubation of NTCA3 with the different cell systems were examined. A ti me-course study in cell whole extracts showed that bacterial and mamma lian cells can acetylate NTCA3 forming 5-acetylamino-3-thiophene-carbo xanilide. The formation of this metabolite in human lymphocyte extract s was not confirmed. These data support the conclusions that: (i) both bacterial and mammalian activation pathways play a role in mutations by NTCA3; (ii) the N-acetylated derivative is generated by acyltransfe rase after reduction and is the end product of the metabolism in both bacterial and mammalian cells; and (iii) different levels of reductase and acetyltransferase activity may contribute to the differential sen sitivity of the different cellular species to the genotoxicity of NTCA 3. The fact that NTCA3 serves as substrate for enzymatic activities of importance also in human metabolism needs consideration in assessing the potential risk posed by NTCAs.