Assessment of potential mutagenic activities of a novel benzothiazole MAO-A inhibitor E2011 using Salmonella typhimurium YG1029

The potential initiation activities of a novel monoamine oxidase type-A (MA O-A) inhibitor E2011, which induced preneoplastic foci in the rat liver, we re investigated by comparing the mutagenic activity of E2011, 6-aminobenzot hiazole (6-ABT, a structural scaffold of E2011) and its derivatives, which are suggested primary reactive metabolites for E2011-induced hepatotoxicity in the rats in vivo, in the Ames assay system employing two Salmonella tes ter strains, TA100 and YG1029, a bacterial O-acetyltransferase-overproducin g strain of TA100. E2011, a tertiary amine, showed no mutagenic activity bo th in the Salmonella typhimurium TA100 and YG1029 with and without S9 mix. On the other hand, a secondary aromatic amine ER-174238-00, a typical decar bonated metabolite of E2011, showed weak but significant mutagenicity in YG 1029 in the presence of S9 mix, and a primary aromatic amine ER-174237-00, an N-dealkylated derivative of ER-174238-00, exhibited S9-dependent potent mutagenicity in YG1029. Thus, it appears that primary and secondary amino m oieties of benzothiazole derivatives at C-6-position are the specific struc tures contributing to their mutagenic activity. In addition, the alkyl grou p at C-2-position of E2011, ER-174237-00 and ER-174238-00 is suggested to i ntensify the mutagenic activity, since the mutagenicity of ER-174237-00 is approximately two-fold higher than that of 6-ABT, which has hydrogen at C2- position in the place of the alkyl group. These results strongly suggest th at E2011 has potential initiation activities in the rat liver in vivo after undergoing decarbonation, one of the metabolic pathways, at the carbonyl m oiety of oxazolidinone ring to form mutagenic amine(s), (C) 2000 Elsevier S cience B.V. All rights reserved.