TY - JOUR
T1 - Chlorination of guanosine and other nucleosides by hypochlorous acid and myeloperoxidase of activated human neutrophils
T2 - Catalysis by nicotine and trimethylamine
AU - Masuda, Mitsuharu
AU - Suzuki, Toshinori
AU - Friesen, Marlin D.
AU - Ravanat, Jean Luc
AU - Cadet, Jean
AU - Pignatelli, Brigitte
AU - Nishino, Hoyoku
AU - Ohshima, Hiroshi
PY - 2001/11/2
Y1 - 2001/11/2
N2 - Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H2O2 and Cl-. We have found that various (2′-deoxy)nucleosides react with HOCl to form chlorinated (2′-deoxy)nucleosides, including novel 8-chloro(2′-deoxy)guanosine, 5-chloro(2′-deoxy)cytidine, and 8-chloro(2′-deoxy)adenosine formed in yields of 1.6, 1.6, and 0.2%, respectively, when 0.5 mM nucleoside reacted with 0.5 mM HOCl at pH 7.4. The relative chlorination, oxidation, and nitration activities of HOCl, myeloperoxidase, and activated human neutrophils in the presence and absence of nitrite were studied by analyzing 8-chloro-, 8-oxo-7,8-dihydro-, and 8-nitroguanosine, respectively, using guanosine as a probe. 8-Chloroguanosine was always more easily formed than 8-oxo-7,8-dihydro- or 8-nitro-guanosine. Using electrospray ionization tandem mass spectrometry, we show that several chlorinated nucleosides including 8-chloro(2′ -deoxy)guanosine are formed following exposure of isolated DNA or RNA to HOCl. Micromolar concentrations of tertiary amines such as nicotine and trimethylamine dramatically enhanced chlorination of free (2′ -deoxy)nucleosides and nucleosides in RNA by HOCl. As the G-463A polymorphism of the MPO gene, which strongly reduces myeloproxidase mRNA expression, is associated with a reduced risk of lung cancer, chlorination damage of DNA/RNA and nucleosides by myeloperoxidase and its enhancement by nicotine may be important in the pathophysiology of human diseases associated with tobacco habits.
AB - Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H2O2 and Cl-. We have found that various (2′-deoxy)nucleosides react with HOCl to form chlorinated (2′-deoxy)nucleosides, including novel 8-chloro(2′-deoxy)guanosine, 5-chloro(2′-deoxy)cytidine, and 8-chloro(2′-deoxy)adenosine formed in yields of 1.6, 1.6, and 0.2%, respectively, when 0.5 mM nucleoside reacted with 0.5 mM HOCl at pH 7.4. The relative chlorination, oxidation, and nitration activities of HOCl, myeloperoxidase, and activated human neutrophils in the presence and absence of nitrite were studied by analyzing 8-chloro-, 8-oxo-7,8-dihydro-, and 8-nitroguanosine, respectively, using guanosine as a probe. 8-Chloroguanosine was always more easily formed than 8-oxo-7,8-dihydro- or 8-nitro-guanosine. Using electrospray ionization tandem mass spectrometry, we show that several chlorinated nucleosides including 8-chloro(2′ -deoxy)guanosine are formed following exposure of isolated DNA or RNA to HOCl. Micromolar concentrations of tertiary amines such as nicotine and trimethylamine dramatically enhanced chlorination of free (2′ -deoxy)nucleosides and nucleosides in RNA by HOCl. As the G-463A polymorphism of the MPO gene, which strongly reduces myeloproxidase mRNA expression, is associated with a reduced risk of lung cancer, chlorination damage of DNA/RNA and nucleosides by myeloperoxidase and its enhancement by nicotine may be important in the pathophysiology of human diseases associated with tobacco habits.
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U2 - 10.1074/jbc.M102700200
DO - 10.1074/jbc.M102700200
M3 - Article
C2 - 11533049
AN - SCOPUS:0035798575
SN - 0021-9258
VL - 276
SP - 40486
EP - 40496
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -