Nitroreductase independent mutagenicity of 1-halogenated-2,4-dinitrobenzenes.
The 1-halogen substituted 2,4-dinitrobenzenes have been found to be mutagenic in Salmonella TA98 with an activity order of 1-fluoro > 1-chloro > 1-bromo > 1-iodo. This specific activity was not lowered in the nitroreductase deficient strain TA98NR and O-acetyltransferase deficient strain TA98/1,8-DNP6, indicating that the mutagenicity of these compounds is not dependent upon -NO2 reduction to -NHOH and its subsequent esterification. The activity was, rather, higher in the former and remained almost equal in the latter strain compared to TA98, suggesting these compounds to react directly with bacterial DNA. Further, the reaction of these halodinitrobenzenes with methionine, at physiological pH, resulting in the formation of 1-S-methyldinitrobenzene showed that these compounds have the ability to attack DNA directly through nucleophilic substitution of the halogen atom and the role of the bacterial nitroreductases for production of mutagenic lesions was not considered. It was, further, proposed that these compounds interact with DNA through SNAr mechanism instead of SN2 cited in literature.
Gupta
R L
RL
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Saini
B H
BH
Juneja
T R
TR
D000477:Alkylating Agents / Q000633:toxicity; D018736:DNA Adducts / Q000633:toxicity; D004136:Dinitrobenzenes / Q000633:toxicity*; D004137:Dinitrochlorobenzene / Q000633:toxicity; D004139:Dinitrofluorobenzene / Q000633:toxicity; D008715:Methionine / Q000378:metabolism / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009601:Nitroreductases / Q000378:metabolism*; D012475:Salmonella / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
D000477:Alkylating Agents; D018736:DNA Adducts; D004136:Dinitrobenzenes; D004137:Dinitrochlorobenzene; D009153:Mutagens; C011688:1-bromo-2,4-dinitrobenzene; C023350:1-iodo-2,4-dinitrobenzene; D008715:Methionine; D004139:Dinitrofluorobenzene; D009601:Nitroreductases