Sa. Malia et Ak. Basu, REDUCTIVE METABOLISM OF 1-NITROPYRENE ACCOMPANIES DEAMINATION OF CYTOSINE, Chemical research in toxicology, 7(6), 1994, pp. 823-828
1-Nitropyrene (1-NP), a common environmental pollutant, is a mutagen a
nd tumorigen. Nitroreduction is a major pathway by which 1-NP is metab
olized. In order to study the mutational specificity of reductively ac
tivated 1-NP, single-stranded M13mp18 DNA was treated with tritium-lab
eled 1-nitrosopyrene in the presence of ascorbic acid to generate N-hy
droxyl-aminopyrene in situ. HPLC analysis of the treated DNA, followin
g enzymatic digestion, showed that >95% of tritium was located in one
major adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene. Transfection of th
ese adducted M13 DNA in Escherichia coli indicated a dose-dependent re
duction in viability with concomitant enhancement in mutagenesis in th
e lacZ gene fragment. Without SOS functions, the major type of mutatio
n was C-->T transition (48%). Further studies have shown that cytosine
deamination occurred during ascorbic acid-induced nitroreduction, whi
ch was likely responsible for the C-->T transitions. Deamination of cy
tosine alco occurred at a significant frequency when nitroreduction of
either 1-NP or 1-nitrosopyrene was catalyzed by xanthine oxidase, a m
ammalian nitroreductase.