Mechanism of DNA binding by the oesophageal carcinogen N-nitroso-N-methylaniline.
N-Nitroso-N-methylaniline (NMA) is a strong oesophageal carcinogen in rats but exhibits few overt genotoxic effects. Previous work from our laboratory established that NMA is readily metabolized by cytochrome P450-catalysed N-demethylation to produce the benzenediazonium ion (BDI), a relatively stable but reactive electrophilic agent. We have also shown that BDI reacts with DNA to form an acid-labile adduct. We have now shown that BDI, generated chemically or by the metabolism of NMA in vitro, reacts with DNA to form a triazene coupling product at the N6-position of adenine residues. This adduct has also been shown to be produced in the liver DNA of rats treated with NMA. Procedures for the isolation of DNA and for analysis of the adduct are presented.
Koepke
S R
SR
Laboratory of Chemical and Physical Carcinogenesis, National Cancer Institute-Frederick Cancer Research and Development Center, MD.
Kroeger-Koepke
M B
MB
Michejda
C J
CJ
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000139:chemically induced*; D009602:Nitrosamines / Q000378:metabolism* / Q000633:toxicity; D051381:Rats
D002273:Carcinogens; D009602:Nitrosamines; D004247:DNA; C014102:N-methyl-N-nitrosoaniline