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.

Myeloperoxidase, released by activated phagocytes, forms reactive oxidants by catalysing the reaction of halide and pseudo-halide ions with H(2)O(2). These oxidants have been linked to tissue damage in a range of inflammatory diseases. With physiological levels of halide and pseudo-halide ions, similar amounts of HOCl (hypochlorous acid) and HOSCN (hypothiocyanous acid) are produced by myeloperoxidase. Although the importance of HOSCN in initiating cellular damage via thiol oxidation is becoming increasingly recognized, there are limited data on the reactions of HOSCN with other targets. In the present study, the products of the reaction of HOSCN with proteins has been studied. With albumin, thiols are oxidized preferentially forming unstable sulfenyl thiocyanate derivatives, as evidenced by the reversible incorporation of (14)C from HOS(14)CN. On consumption of the HSA (human serum albumin) free thiol group, the formation of stable (14)C-containing products and oxidation of tryptophan residues are observed. Oxidation of tryptophan residues is observed on reaction of HOSCN with other proteins (including myoglobin, lysozyme and trypsin inhibitor), but not free tryptophan, or tryptophan-containing peptides. Peptide mass mapping studies with HOSCN-treated myoglobin, showed the addition of two oxygen atoms on either Trp(7) or Trp(14) with equimolar or less oxidant, and the addition of a further two oxygen atoms to the other tryptophan with higher oxidant concentrations (> or = 2-fold). Tryptophan oxidation was observed on treating myoglobin with HOSCN in the presence of glutathione and ascorbate. Thus tryptophan residues are likely to be favourable targets for the reaction in biological systems, and the oxidation products formed may be useful biomarkers of HOSCN-mediated protein oxidation.

Nocturia is a bothersome and highly prevalent urological condition characterised by the need to wake to void at night. Contrary to popular misconception, nocturia is equally common in men and women, and although its prevalence increases with age, a significant proportion of younger people are also affected. Nocturia leads to repeated fragmentation of sleep and consequently to a serious decline in daytime functioning and in overall quality of life and health. As such, its impact should not be underestimated by clinicians. Traditionally, nocturia has been regarded as a symptom of benign prostatic enlargement and/or overactive bladder syndrome, with treatment therefore directed towards increasing the capacity of the bladder to hold urine. Such treatments have proven largely ineffective in many patients, likely because nocturnal polyuria (NP), a condition that results in overproduction of urine at night, has been found to be present in the majority of nocturia patients. As such, the traditional belief that nocturia is attributable to some other underlying pathological factors, is now being replaced by the acknowledgment that it can be a distinct clinical entity with specific pathogenesis. Frequency‐volume charts are an invaluable tool, recommended for routine use in clinical practice, to determine whether nocturia is a result of excessive urine production at night, or of small voided volumes (indicating bladder storage problems), or indeed a combination of these factors. Given the specific antidiuretic action of desmopressin, a synthetic analogue of the body’s own antidiuretic hormone, it should be considered as first‐line therapy for patients with nocturia where NP is present.

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Objective-Oxidized lipids and proteins, as well as decreased antioxidant levels, have been detected in human atherosclerotic lesions, with oxidation catalyzed by iron and copper postulated to contribute to lesion development. Zinc has been postulated to displace iron from critical sites and thereby protect against damage. In this study, metal ion and protein oxidation levels were quantified in human carotid and abdominal artery specimens containing early-to-advanced lesions, to determine whether zinc concentrations correlate inversely with iron levels and protein oxidation. Methods and Results-Metal ions were quantified by EPR and inductively coupled plasma mass spectroscopy. Native and oxidized protein side-chains were quantified by high-performance liquid chromatography. A therosclerosis is a multifactorial disease to which many factors contribute; defining the role of each of these has proved to be problematic. Oxidation, and in particular that of low-density lipoproteins (LDL), has been linked to disease development, 1 although the significance of this process has not been fully established (reviewed 2 ). Previous studies have variously implicated lipoxygenase, peroxynitrite, myeloperoxidase, oxygen radicals, and metal-ions in lesion oxidation (reviewed 2 ). In the case of metal ions, a correlation between iron accumulation and the extent of protein (but not lipid) oxidation has been reported for human lesions. 3 Cholesterol ester and cholesterol accumulation also correlate positively with iron, suggesting that these processes are interlinked. 3,4 These data are consistent with some, but not all, epidemiological studies on the potential links between iron and cardiovascular disease. [5][6][7][8] Zinc ions have been reported to modulate oxidant damage via the displacement of iron and copper from oxidationsensitive sites on erythrocyte membranes, 9 LDL, 10 or liposomes. 11 Epidemiological data indicate that elevated serum zinc levels may be protective against disease. 12 Serum or plasma measurements of zinc in people with established atherosclerosis indicate that low zinc levels are associated with increased disease 13,14 and a postmortem study has reported lower tissue levels of zinc in the abdominal aorta of patients who died of heart disease compared to other causes. 15 In contrast, zinc supplementation of the human diet does not affect the susceptibility of LDL to oxidation ex vivo 16,17 or the concentrations of LDL-cholesterol, total cholesterol, or triglycerides, but has an adverse effect on high-density lipoprotein levels, suggesting that high serum zinc levels may promote disease. 17 Elevated zinc may stimulate the formation of oxidants and inhibit protective enzymes in some cells. 18 Atherosclerotic lesions of cholesterol-fed rabbits contain elevated levels of iron and reduced levels of zinc. 19 -21 Zinc supplementation, via dietary feeding, reduced lesion area despite insignificant changes in lesion zinc concentrations; these changes were ascribed to a displacement of iron by zinc. 20 Zinc supplement...