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Download Article (PDF) Widner et at. : Neopterin: indicator of oxidative stress and part of the cytotoxic armature Pteridines Vol. 9,1998, pp. 91 ·· 102 N eopterin: Indicator of Oxidative Stress and Part of the Cytotoxic Armature of Activated Macrophages in Humans Bernhard Widner, Gabriele Baier-Bitterlich, Irene Wede, Barbara Wirleitner, Helmut Wachter, Dietmar Fuchs§ Institute of Medical Chemistry and Biochemistry, University of Innsbruck, and Ludwig Boltzmann In­ stitute for AlDS-Research Fritz Pregl Strasse 3 A-6020 Innsbruck, Austria , Received November 30, 1997) Introduction artherosclerosis, cardiac diseases, or inflammatory bowel disease. Reactive oxygen species are formed by cells in Recent studies provide evidence that pteridine the course of biochemical redox reactions, in­ derivatives are able to interfere with redox systems \'()Iving oxygen as part of the normal metabolism. and hence may influence cell homeostasis and in­ In addition, exogeneous stimuli like UV light or tracellular signal transduction pathways. ionizing radiation lead to the production of free radical species. Furthermore, phagocytes and vari­ Neopterin ous other immunocompetent cells form and release reactive species as part of their cytotoxic re­ Neopterin is produced in large amounts by ac­ pertoire to guarantee self integrity under con­ tivated human monocytes/ macrophages (1 ). The ditions of oxidative stress. Due to overwhelming enzyme GTP-cyclohydrolase I converts the nu­ formation of reactive species, a series of antioxi­ cleotide guanosinetriphosphate (GTP) to form 7 , dative defense mechanisms is established in cells, 8-dihydroneopterintriphosphate (Fig. 1). The latt­ including low molecular mass compounds like as­ er intermediate is transformed by 6-pyruvoyltetra­ corbic acid, tocopherol, or reduced glutathion, de­ hydropterin synthase ( PTPS) and sepiapterin toxyfYing enzymes, e.g., superoxide dismutase, reductase to 5,6,7,8-tetrahydrobiopterin, an essen­ and a set of repairing enzymes, restoring damaged tial co-factor for certain mono-oxygenases (2), e . DNA. For homeostasis, cells have to maintain an g ., phenylalanine- and tyrosine hydroxylase, tryp­ appropriate balance between oxidative and antioxi­ tophan-5-hydroxylase, and for nitric oxide syn­ dative processes. Overproduction of reactive spec­ thase (NOS) (3,4). In various cells, GTP-cyclo­ ies or, respectively, diminution of the antioxida­ hydrolase I activity can be stimulated when ex­ tive repertoire causes o xidative stress which may posed to the cytokine interferon-y (IFN-y). There­ lead to cell death and tissue injury. by in most cells tetrahydrobiopterin accumulates. Large quantities of reactive compounds are pro­ In human monocytes/ macrophages, the constitu­ duced during immune reactions, hence the over­ tive activity of PTPS is low, and as a consequence, production of free radicals and, respectively, ox­ an excess of 7,8-dihydroneopterin and neopterin idative stress are implicated in a variety of quite over biopterin is produced (5). The ratio of 7,8- heterogeneous diseases, e.g. rheumatoid arthritis, dihydroneopterin and neopterin is about 3:1 in ar­ adult respiratory distress syndrome, cystic fibrosis, terial blood and in urine and about 2 : 1 in venous § Author to whom correspondence should be addressed. blood (6,7,8). * Dedicated to the 70th birthday of Prof. Wolfgang Pt1ei · IFN -y is excreted by activated NK cells and by derer, Konstanz, Germany T-helper lymphocytes, when the cellular immune Pteridines/ Vol. 9 / No. 2 92 Widner et al.: Neopterin: indicator of o'XidclL \ c < ro:''' clIld part of the cytotoxic armature amounts by mOI1ocnes/ macrophages, when the cellular immune s\stem is activated (9). Along this line, the concentration of neopterin and 7,8- dihydroneopterin in human body t1uids like blood and urine ref1ccts the <lCtivation degree of T -help­ er cells and monocytes/macrophages within the scope of a comprehensive immunological network (10). Thus, in particular, viral infections, autoim­ mune diseases and various malignant tumors are 0 NnOHOPP" associated with increased concentrations of HN :):I '" OH neopterin derivatives (9,11-13). Increased neopte­ H,N A N N H H rin concentrations indicate cell mediated immune 7.8-<lihydroneopterintriphosphate activation, and therefore neopterin is proved as immune system parameter, reHecting the extent phO~~8se / ~ 6-PTPS and the activity of diseases and predicting prog­ OXid8'/ ~pterin nosis in, e.g., HIV infection or malignant dis­ eases (Table 1). 0 Nr):°H CH,OH Reactive species HN '" :): HN~~~CH3 A I"" OH A)L j 6H H2N N N H,N N N H The term 'reactive species comprises small ox­ neopterin 5.6,7.8-tetrahydrobiopterin ygen-, chlorine-, and nitrogen-containing molec­ Bigure 1. The pathway to the formation of neopterin ules, most of which possessing cytotoxic capacity, derivatives in monocytes/macrophages. Interferon-y ac­ e.g., hydrogen peroxide (H20 2 ), superoxide anion tivates GTP-cyclohydrolase I. In human monocytes/ma­ (0 ), nitric oxide (NO), peroxynitrite (ONOO), crophages, constitutive activities of the subsequent en­ 2 or hypochlorite (OCl) (Table 2, Refs. 14,15). zymes 6-pyruvoyltetrahydropterin synthase and sepi­ apterin reductase are low, leading to overwhelming for­ Reactive species are formed by various cell-types, mation of neopterin. including phagocytes (16), vascular endothelial cells (17,18,19), fibroblasts (20), lymphocytes (21), and macrophages (221, mostly as secondary products of system is stimulated. Together with other cyto­ cellular metabolism, and they may be regarded as a kines, e.g., tumor necrosis factor alpha (TNF-a), consequence from the utilization of molecular ox­ or interleukin 2 (IL-2), IFN -y acts synergistically, ygen by aerobic organisms. However, more im­ enhancing cellular immune response. As a conse­ portantly, large quantities of reactive molecules, in quence, neopterin derivatives are excreted in large particular superoxide anion and nitric oxide, are Table 1. Neopterin concentrations in diseases linked with oxidative stress Increased neopterin production allograft rejection autoimmune diseases e.g. rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, multiple sclerosis malignant diseases e .g. gynaecological carcinoma, ovarian carcinoma, haematological neoplasias, urogenital tract cancer, cancer of the prostata, hepatocellular carcinoma, lung cancer, gastointestinal cancer, hepatic cancer infectious diseases e.g. viruses (hepatitis,HIV-infection), intracellular protozoa (malaria, schistosomiasis mansoni), intracellular bacteria (pulmonary tubercolosis, leprosy, melioidosis) cardiac disorders myocardial infarction, congestive heart failure, acute rheumatic fever neurodegenerative disorders e.g. Alzheimer's disease Normal neopterin production Duchenne's muscular dystrophy motor neuron disease Pteridines/ Vol. 9 / No. 2 Widner et at.: Neopterin: indicator of oxidative stress and part of the cytotoxic armature 93 Table 2. Reactive oxygen and nitrogen species as part of cytotoxic armature and antioxidative defense Radicals Non-radicals HydroA),1 on Hydrogen peroxide H 20 2 Alkoxyl RO Hypochlorous acid HOCI Hydroperoxyl H02 Ozone 0, Peroxyl R02 Singlet oxygen l~g O 2 Superoxide anion O 2 Peroxynitrite ONOO' Nitric oxide NO Nitrosyl NO' Nitrogen dioxide N02 Nitroxide NO + NitroniuJ11 N02 Nitrous acid HN02 Nitrogen oxides N,Ov released from activated immunocompetent cells as is generated by consecutive reactions of the above­ part of their cytotoxic armature. For example, upon mentioned species, including nearly all oxidation IFN-y stimulation, macrophages are primed to pro­ states of oxygen and nitrogen (41). Due to the duce reactive oxygen species (ROS), obviously fast reaction rates, it is difficult to examine the \\'ithin the scope of a cellular immune response chemical nature of all these reactive species which · 23). Superoxide anion is generated in vivo, when are involved in cytotoxic processes. fundamental molecules in metabolism, including ca­ Peroxynitrite is formed in a very fast reaction techolamines, tetrahydrofOlates, reduced Havines, or from nitric oxide and superoxide anion (42). Its .xanthine, are directly aflected by oxygen. Mono-ox­ half life at physiological conditions is 1 s. When \'genases are involved in these, partly auto-oxidative peroxynitrite is protonated, a series of extremly processes, as released superoxide anion is applied reactive species is formed intermediately (43,44), for further oxidation. Interestingly, the formation and aromatic structures (45,46), thiol groups (47), of superoxide also seems to be connected with desoxyribose (48), and lipids (49) are rapidly af­ 'leakages' in mitochondrial electron transport chains fected. At physiological pH of 7.4, the nitrating 24). A series of authors described toxic eflects of potential of peroxynitrite has been found to be superoxide anion on biologic systems (25-30). maximum; the reactive intermediate involved is Nitric oxide is enzymatically formed by many described as nitronium-like ion, NO/ (50). Ac­ ..:ell types. Nitric oxide synthase utilizes molecular tually, 3-nitrotyrosine, the nitration product of oxygen to oxidize the side chain of arginine, form­ tyrosine, has been found in diseases, when the im­ i ng citrullin and nitric oxide (31). Nitric oxide rad­ mune system is activated [e.g., in rheumatoid ical plays an important physiological role in signal arthritis (51), severe lung injuries (52), or coro­ transduction, controlling blood pressure by vaso­ nary heart diseases (53)],
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