title: 2-Nitrosoamino-3-methylimidazo[4,5-f]quinoline stability and reactivity.
abstract: N-Nitrosamines and nitrosamides can initiate cancer. These studies evaluated the stability and reactivity of 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) to assess its possible role in the initiation of colon cancer by 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). (14)C-N-NO-IQ was incubated with different solvents and pHs in the presence and in the absence of nucleophiles and analyzed by HPLC. The products identified by electrospray ionization mass spectrometry include 2-chloro-3-methylimidazo[4,5-f]quinoline (2-Cl-IQ), 2,2'-azo-3,3'-dimethylimidazo[4,5-f]quinoline (AZO-IQ), 2-azido-IQ (2-N(3)-IQ), 3-methylimidazo[4,5-f]quinoline (deamino-IQ), and IQ. A variety of organic solvents were tested with 0.1 N HCl. 2-Cl-IQ and IQ were formed following acidification of all solvents. AZO-IQ was only formed in methanol. Deamino-IQ was the major product formed in all of the alcohols tested, except for methanol. Under acidic conditions that completely convert N-NO-IQ in 5 min (acetonitrile with 0.1 N HCl), 62% of N-NO-IQ remains after 30 min if dimethyl sulfoxide is substituted for acetonitrile. N-NO-IQ was stable in the physiologic pH range of 5.5-9.0 and did not react with nucleophiles over a 4 h period at pH 7.4 and 37 degrees C. At acidic pH (pH < or =2.0) for 30 min and 37 degrees C, N-NO-IQ becomes labile forming electrophile(s), which combine with biologically relevant nucleophiles. The reaction of N-NO-IQ at pH 2.0 followed first-order kinetics (t(1/2) = 10 +/- 2 min) and was significantly increased in 10 mM NaN(3) (t(1/2) = 2 +/- 0.1 min). 2-N(3)-IQ was the major product observed in the latter incubation. N-NO-IQ binding to DNA at pH 2.0 is 100-fold more than that at pH 7.4. At pH 2.0, greater than 90% of the binding was inhibited by 10 mM NaN(3). Thus, N-NO-IQ forms a reactive electrophile(s) at acidic pH, which binds DNA. N-NO-IQ reaction products may depend on the pH and the hydrophobic milieu of cells or tissues.
authors.affiliation: Division of Geriatric Medicine, VA Medical Center, Missouri 63125, USA.
authors.forename: Vijaya M
authors.initials: VM
authors.lastname: Lakshmi
authors.forename: Fong Fu
authors.initials: FF
authors.lastname: Hsu
authors.forename: Terry V
authors.initials: TV
authors.lastname: Zenser
mesh_terms: D000097:Acetonitriles / Q000737:chemistry*; D002273:Carcinogens / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000097:Acetonitriles; D002273:Carcinogens; D011804:Quinolines; C055822:2-azido-3-methylimidzo(4,5-f)quinoline; D004247:DNA; D004121:Dimethyl Sulfoxide; C032159:acetonitrile