Myeloperoxidase is a
heme enzyme released by activated phagocytes that is responsible for the generation of the strong
oxidant hypochlorous acid (HOCl). Although HOCl has potent bactericidal properties and plays an important role in the human immune system, this
oxidant also causes damage to tissues, particularly under inflammatory conditions. There is a strong link between chronic
inflammation and the incidence of many
cancers, which may be associated with the ability of HOCl and related
oxidants such as N-
chloramines to damage
DNA. However, in contrast to HOCl, little is known about the reactivity of N-
chloramines with
DNA and its constituents. In this study, we examine the ability of HOCl and various N-
chloramines to form chlorinated base products on
nucleosides,
nucleotides,
DNA, and in cellular systems. Experiments were performed with N-
chloramines formed on Nalpha-acetyl-
histidine (His-C), Nalpha-acetyl-
lysine (Lys-C),
glycine (Gly-C),
taurine (Tau-C), and
ammonia (Mono-C). Treatment of
DNA and related materials with HOCl and His-C resulted in the formation of
5-chloro-2'-deoxycytidine (5CldC),
8-chloro-2'-deoxyadenosine (8CldA) and
8-chloro-2'-deoxyguanosine (8CldG). With the
nucleosides, 8CldG was the favored product in each case, and HOCl was the most efficient chlorinating agent. 5Cl(d)C was the most abundant product on exposure of the
nucleotides and
DNA to HOCl and His-C, with only low levels of chlorinated products observed with Lys-C, Gly-C, Tau-C, and Mono-C. 5CldC was also formed on exposure of smooth muscle cells to either HOCl or His-C. Cellular
RNA was also a target for HOCl and His-C, with evidence for the formation of 5-chloro-cytidine (5ClC). This study shows that HOCl and the model N-
chloramine, His-C, are able to chlorinate cellular genetic material, which may play a role in the development of various inflammatory
cancers.