title: Analysis of metabolism and genotoxicity of 5-nitro-3-thiophenecarboxanilides in bacterial, mammalian and human cells.
abstract: 5-nitro-3-thiophenecarboxanilide (NTCA3) was clearly mutagenic in Salmonella typhimurium strains TA98, YG1021 (the strain with elevated nitroreductase) and YG1024 (the strain with elevated O-acetyltransferase) and only slightly mutagenic at the gpt locus in AS52 cells. Clastogenic activity in human lymphocytes was dependent on the length of exposure: detectable chromosome aberrations were observed following a 24 h treatment period, but not after 3 h exposure. S9 increased genotoxicity in both mammalian cells and human lymphocytes. Metabolites formed by incubation of NTCA3 with the different cell systems were examined. A time-course study in cell whole extracts showed that bacterial and mammalian cells can acetylate NTCA3 forming 5-acetylamino-3-thiophene-carboxanilide. The formation of this metabolite in human lymphocyte extracts 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 acyl-transferase 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 sensitivity of the different cellular species to the genotoxicity of NTCA3. 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.
authors.affiliation: Dipartimento di Farmacologia, Università di Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Hrelia
authors.forename: F
authors.initials: F
authors.lastname: Vigagni
authors.forename: F
authors.initials: F
authors.lastname: Maffei
authors.forename: C
authors.initials: C
authors.lastname: Fimognari
authors.forename: L
authors.initials: L
authors.lastname: Lamartina
authors.forename: D
authors.initials: D
authors.lastname: Spinelli
authors.forename: P
authors.initials: P
authors.lastname: Juric
authors.forename: M C
authors.initials: MC
authors.lastname: Guerra
authors.forename: G
authors.initials: G
authors.lastname: Cantelli-Forti
mesh_terms: D000115:Acetylesterase / Q000378:metabolism; D000813:Anilides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002869:Chromosome Aberrations; D006801:Humans; D066298:In Vitro Techniques; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism* / Q000633:toxicity*; D009601:Nitroreductases / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D000813:Anilides; D009153:Mutagens; D009601:Nitroreductases; D000115:Acetylesterase