Influence of nitroreductase and O-acetyltransferase on the mutagenicity of substituted nitrobenzothiophenamines in Salmonella typhimurium.
The mutagenic activity of 17 substituted (aryl)(2-nitrobenzo[b]thiophen-3yl)amines has been evaluated in the Ames test with different isogenic strains of Salmonella typhimurium, that varied in their expression of nitroreductase and O-acetyltransferase. Active derivatives induced frameshift mutations in TA98 strain, and differences in the chemical structure resulted in up to 15-fold changes in mutagenic activity. The non-mutagenic compounds are the unsubstituted parent compound and derivatives with para-chloro, para-fluoro, para-diethylamino, meta-bromo and para-dimethylamino groups. They do not show any activity even in strains with higher level of nitroreductase or O-acetyltransferase. The addition of S9 fraction decreases the mutagenic potential or gives comparable results to those obtained without metabolic activation. For electron-donating substituents, the meta-isomers display the greatest mutagenic potency, whereas the transfer of the group to the para-position leads to less active or unactive molecules. All active nitrobenzothiophenes are substrates for bacterial nitroreductase and O-acetyltransferase, as shown by the reduced mutagenicity in the deficient strains and increased mutagenicity in the corresponding overproducing bacteria. Previous reports have pointed out interest in nitrothiophene analogues with para-chloro and para-fluoro substituents as promising anti-inflammatory drugs. The present study further enhances the putative interest in these derivatives, based on absence of mutagenicity.
Hrelia
P
P
Dipartimento di Farmacologia, Università di Bologna, Italy. phrelia@biocfarm.unibo.it
Fimognari
C
C
Maffei
F
F
Spinelli
D
D
Lamartina
L
L
Sarvà
M C
MC
Cantelli Forti
G
G
D000123:Acetyltransferases / Q000494:pharmacology*; D000588:Amines / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009601:Nitroreductases / Q000494:pharmacology*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013876:Thiophenes / Q000633:toxicity*
D000588:Amines; D009153:Mutagens; D013876:Thiophenes; D009601:Nitroreductases; D000123:Acetyltransferases