Mutagenic activity of 2-chloro-4-nitroaniline and 5-chlorosalicylic acid in Salmonella typhimurium: two possible metabolites of niclosamide.
Niclosamide is an anti-helminthic drug susceptible to being metabolized into a bacterial mutagen by the action of enzymes present in the S9 activation mixture. Additional results from genotoxic studies in rodents and humans suggest that the drug is absorbed from the gastrointestinal tract, and mutagenic metabolites are excreted both in the free form and as conjugated glucuronides. As in the case of other secondary amides, phase I metabolism of niclosamide may result in a hydrolytic cleavage of the amide bond, giving rise to 5-chlorosalicylic acid and 2-chloro-4-nitroaniline as the main metabolites. In this study, the mutagenicity of these compounds was tested using the Salmonella typhimurium assay. Bacterial mutagenicity tests with these 2 compounds reveal a non-mutagenic response with 5-chlorosalicylic acid and a mutagenic one with 2-chloro-4-nitroaniline. However, the mutagenic potency observed with this compound is lower than that of niclosamide. The role of nitroreduction in the activation of niclosamide and 2-chloro-4-nitroaniline was also investigated with the help of S. typhimurium strains TA98NR, YG1020, YG1021 and YG1024. The results show a pattern of response which is qualitatively similar for both compounds and this indicates that its mutagenicity depends on both nitroreduction and transacetylation.
Espinosa-Aguirre
J J
JJ
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, D.F.
Reyes
R E
RE
Cortinas de Nava
C
C
D000814:Aniline Compounds / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D015394:Molecular Structure; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D009534:Niclosamide / Q000378:metabolism / Q000633:toxicity*; D010084:Oxidation-Reduction; D012459:Salicylates / Q000378:metabolism / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects
D000814:Aniline Compounds; D009153:Mutagens; D012459:Salicylates; C071396:2-chloro-4-nitroaniline; D009534:Niclosamide; C015751:5-chlorosalicylic acid