Metabolism of 1,8-dinitropyrene by Salmonella typhimurium.
Earlier work has shown that many nitroaromatic and nitroheterocyclic compounds are directly 'activated' to their ultimate mutagenic forms through the action of bacterial nitroreductase enzymes. However, in the case of 1,8-dinitropyrene (DNP) and certain other nitroarenes the pathway of activation is more complex and neither the identity of the ultimate mutagens nor the nature of the DNA adducts formed are known. We now show that Salmonella typhimurium strains TA98 and TA1538, which are sensitive to DNP and have wild type nitroreductase complements, do metabolize DNP to 1-amino-8-nitropyrene (ANP) and 1,8- diaminopyrene (DAP) but that these compounds are much weaker mutagens than DNP. These two strains (TA98 and TA1538) contain two separable components of nitroreductase activity as determined using nitrofurazone as the substrate. The major component, at least, is capable of reducing both 1-nitropyrene (NP) and DNP although the rates are much lower than with nitrofurazone. TA98NR , a mutant of TA98 that is resistant to nitrofurazone and NP but not to DNP, lacked the major nitroreductase but retained two minor components. In contrast, a mutant ( DNP6 ) which is resistant to DNP (but not to NP) contained a full complement of nitroreductases. When the metabolism of [3H]DNP by crude extracts of TA98 was re-examined, previously undetected metabolites were found. These were more polar than DAP and ANP and were also seen when TA98NR was used as the source of enzyme. These metabolites were not formed when enzymes from TA98DNP6 or TA98NR / DNP6 were used. This work supports the notion that some enzymic activity other than (or in addition to) nitroreductase is required for the activation of DNP and that the new polar metabolites may be related to this process.
D002851:Chromatography, High Pressure Liquid; D013058:Mass Spectrometry; D009153:Mutagens / Q000378:metabolism*; D009601:Nitroreductases; D010088:Oxidoreductases / Q000378:metabolism*; D011721:Pyrenes / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000378:metabolism*; D013045:Species Specificity; D014316:Tritium; D014969:Xanthine Oxidase / Q000378:metabolism
D009153:Mutagens; D011721:Pyrenes; D014316:Tritium; C033310:1,8-dinitropyrene; D010088:Oxidoreductases; D014969:Xanthine Oxidase; D009601:Nitroreductases