Chlorination of guanosine and other nucleosides by Hypochlorous Acid and Myeloperoxidase of Activated Human Neutrophils

Mitsuharu Masuda (1) , Toshinori Suzuki (1) , Marlin Friesen (2) , Jean-Luc Ravanat (3, 4) , Jean Cadet (4) , Brigitte Pignatelli (1) , Hoyoku Nishino (5) , Hiroshi Ohshima (1)

1 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
2 Unit of nutritional cancer
3 CIBEST - Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie
4 LAN - Laboratoire Lésions des Acides Nucléiques
5 Kyoto Prefectural University of Medicine [Kyoto, Japon]

Activated human neutrophils secrete myeloperoxidase, which generates HOCl from H$_2$O$_2$ 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.

Domaines: Chimie organique

Mitsuharu Masuda, Toshinori Suzuki, Marlin Friesen, Jean-Luc Ravanat, Jean Cadet, et al.. Chlorination of guanosine and other nucleosides by Hypochlorous Acid and Myeloperoxidase of Activated Human Neutrophils: Catalysis by nicotine and trimethylamine. Journal of Biological Chemistry, 2001, 276 (44), pp.40486-40496. ⟨10.1074/jbc.M102700200⟩. ⟨hal-03391030⟩