Chlorination of guanosine and other nucleosides by hypochlorous acid and myeloperoxidase of activated human neutrophils: Catalysis by nicotine and trimethylamine

Mitsuharu Masuda, Toshinori Suzuki, Marlin D. Friesen, Jean Luc Ravanat, Jean Cadet, Brigitte Pignatelli, Hoyoku Nishino, Hiroshi Ohshima

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)40486-40496
Number of pages11
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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